RARE DISEASE
Peutz-Jeghers syndrome
Peutz-Jeghers syndrome
Peutz-Jeghers syndrome
Synonyms: Hamartomatous intestinal polyposis, PJS
Synonyms: Hamartomatous intestinal polyposis, PJS
Synonyms: Hamartomatous intestinal polyposis, PJS
Drug discovery
0
drugs
With orphan designations
Overview
Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder caused by STK11 mutations, characterized by hamartomatous gastrointestinal polyps and mucocutaneous hyperpigmentation. Polyps cause complications like bowel obstruction and intussusception, often presenting in childhood. Patients face elevated cancer risks (gastrointestinal, pancreatic, breast, ovarian), with a cumulative lifetime cancer risk of up to 85% [1][2][15]. Diagnosis combines clinical findings, histopathology, and genetic testing [4][7].
Burden
Cancer: Cumulative risk of 57% by age 70 for GI cancers, 32–54% for breast cancer, and 11–36% for pancreatic cancer [15][2][7].
Morbidity: Recurrent bowel obstructions, anemia, and emergency surgeries in childhood [4][8][10].
Psychosocial impact: Chronic pain, anxiety from surveillance, and visible pigmentation [2][15].
Therapies
Surveillance: Endoscopic polypectomy (via double-balloon enteroscopy or intraoperative methods) to prevent obstruction [3][8][10]; cancer screening (e.g., colonoscopy, breast MRI, pancreatic imaging) starting in childhood/adolescence [7][11][15].
Surgery: Reserved for symptomatic polyps, intussusception, or malignancies [3][8][16].
Genetic counseling: Mandatory for families, with STK11 testing to guide surveillance [7][11].
Categories: rare developmental anomalies during embryogenesis, rare gastroenterological diseases, rare genetic diseases, rare neoplastic diseases, rare skin diseases, rare transplant-related disorders
Research Papers
395 drug discovery papers about Peutz-Jeghers syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
395 drug discovery papers about Peutz-Jeghers syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-15 | STK11/LKB1 Loss in Cancer: From Developmental Constraint to Stress-Adapted Malignancy.
Peutz-Jeghers syndrome (PJS) presents an apparent biological paradox: heterozygous germline pathogenic variants in STK11 predispose to predominantly benign hamartomatous growth while conferring a markedly elevated lifetime risk of cancer, whereas somatic STK11 inactivation in established tumors is frequently associated with aggressive progression and therapeutic resistance. STK11 encodes liver kinase B1 (LKB1), a serine/threonine kinase that integrates metabolic, oxidative, architectural, and immune stress responses. Rather than acting solely as a direct brake on proliferation, LKB1 couples cellular growth, survival, and tissue organization to environmental fitness. We therefore propose a context-dependent stress adaptation framework in which impairment of STK11/LKB1 signaling relaxes stress-imposed constraints on cellular fitness, while the ultimate biological outcome is determined by allelic status, tissue context, and cooperating genetic alterations. In PJS, a heterozygous germline STK11 pathogenic variant creates a constitutional cancer predisposed state in which one functional allele is initially retained, although subsequent loss or impairment of the remaining allele may occur during tumor evolution. In sporadic cancers, somatic STK11 inactivation is often biallelic and frequently cooperates with alterations in KRAS, KEAP1, TP53, NF1, or PI3K-pathway genes. These genetic contexts can promote metabolic reprogramming, redox adaptation, autophagy dependence, immune exclusion, cellular plasticity, and therapeutic resistance, with the strongest mechanistic and clinical evidence currently derived from lung adenocarcinoma (LUAD). Within this framework, enhanced persistence under metabolic, oxidative, immune, and therapy-induced stress does not exclude proliferative effects of STK11 loss but provides a permissive background upon which cooperating oncogenic programs can drive clonal expansion and malignant progression. Stress adaptation creates dependencies on interconnected buffering systems, including antioxidant defenses, autophagy, metabolic plasticity, and ferroptosis suppression. Therapeutic strategies that simultaneously disrupt multiple compensatory pathways may therefore exceed tumor adaptive capacity, convert stress tolerance into therapeutic vulnerability, and provide a rational framework for treating LKB1-deficient tumors and other stress-adapted cancers.
2026-06-22 | Distinct mucosa-associated microbiota signatures and dysbiosis in Peutz-Jeghers syndrome polyps versus paired normal mucosa
Background Peutz-Jeghers syndrome (PJS) is an STK11/LKB1 -mutated autosomal dominant disorder with gastrointestinal hamartomatous polyps and elevated cancer risk, but the role of mucosa-associated microbiota in PJS polyp pathogenesis remains unclear. Aim To investigate the mucosal microbial signatures, dysbiosis characteristics, and potential biomarkers in PJS polyps versus paired normal small intestinal mucosa. Methods A paired-sample design was adopted, enrolling 44 genetically confirmed PJS patients. Mucosa-associated microbiota was profiled via 5R 16S rRNA gene sequencing. Statistical analyses included Wilcoxon rank-sum test, ANOSIM, Spearman’s correlation, and random forest modeling. Results Alpha diversity (Observed species, Chao1, Shannon) was markedly reduced in polyps (all P < 0.001), while Simpson index increased (P < 0.001). Beta diversity differed significantly between groups (ANOSIM, R = 0.0667, P = 0.002). Polyps were enriched in Pseudomonadota (70.00% vs. 49.51%, P < 0.001) and depleted in Bacillota , Bacteroidota (both P < 0.001). Microbial dysbiosis index (MDI) was higher in polyps (P < 0.001). A 9-genera random forest model achieved AUC = 0.897. Escherichia-Shigella correlated with polyp number (P < 0.05), and Enterococcus correlated with CA72–4 levels (P < 0.05). Conclusion PJS polyps exhibit significant mucosal microbial dysbiosis, which may serve as potential biomarkers and therapeutic targets for PJS.
2026-05-25 | Adrenocortical Carcinoma in Peutz-Jeghers Syndrome With a Rare STK11 Pathogenic Germline Variant: A Case Report.
Peutz-Jeghers syndrome (PJS) is an inherited, autosomal-dominant condition, featuring STK11 germline mutations, characterized by hamartomatous gastrointestinal polyps and increased cancer risk. The most commonly associated malignancies are gastrointestinal, pancreatic, and breast cancers. Herein, we report an extremely rare case of PJS with adrenocortical carcinoma (ACC). A 40-year-old woman was referred to University of Tsukuba Hospital with uncontrolled diabetes mellitus (DM) and hypokalemia in July 2021. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a 12 cm mass in the right adrenal gland and aortocaval lymph node swelling. Mucocutaneous hyperpigmentation in her lips and fingertips was observed, and multiple stomach and small intestine polyps were visible on CT. We performed open right adrenalectomy with right nephrectomy, partial hepatectomy, and aortocaval lymph node dissection before diagnosing ACC with lymph node metastasis from the pathology. After surgery, multiple lung and liver metastases developed, and combination chemotherapy (etoposide, doxorubicin, and cisplatin, plus mitotane) was started, achieving stable disease for 2 years. We also performed an OncoGuide NCC Oncopanel on the adrenal tumor specimen and blood sample, revealing a rarely reported pathogenic germline variant (c.394T>C, p.C132R) in STK11. This variant was registered as Likely Pathogenic in the NIH Clinvar public database, which led to a PJS diagnosis. This is the second report of ACC associated PJS in a rare germline variant of STK11. Although rare, loss of STK11 function may lead to cancers outside expected sites in PJS cases.
2026-05-05 | Phosphoproteomic and kinase networks reveal partial EMT and stress-adaptive growth programs in pediatric Peutz-Jeghers polyps.
Peutz-Jeghers syndrome (PJS) is a rare inherited cancer predisposing disorder associated with pathogenic variants of the Serine Threonine Kinase11 (STK11 / LKB1). Morbidity in children is driven by small intestinal obstruction from polyps. The molecular mechanisms driving polyp initiation and growth are poorly understood. We hypothesized that integrated phosphoproteomic analysis of pediatric Peutz-Jeghers polyps would reveal signaling networks driving polyp growth. Intestinal polyp and adjacent non-polyp mucosa from pediatric PJS patients undergoing therapeutic endoscopy-polypectomy underwent mass spectrometry-based proteomic and phosphoproteomic profiling. A bioinformatic pipeline and network analyses were performed to identify differential kinase activity, phosphopeptide enrichment, and signaling nodes relevant to polyp growth. Polyp tissue was enriched for proliferative signaling and biosynthetic drivers, including CLK1 and PKCβ, MAPK10, and MAPK11. Non-polyp mucosa however, exhibited higher expression of regulatory kinases such as HIPK2, PLK2, LATS1, STK38, and PRKCZ/PRKCI, reinforcing apoptosis, polarity, and Wnt/mTOR restraint. Phosphoproteomic networks in polyps support a partial epithelial-mesenchymal transition phenotype, amplified transcription and translation, and a survival shift from BAD-14-3-3 signaling toward YAP/mTOR/NF-kB. PJS polyps display a unique proteomic and phosphoproteomic signature that critically distinguishes PJS from other polyposis syndromes potentially lessening repeated invasive interventions in affected children. Small intestinal pediatric Peutz-Jeghers polyps express a distinct phosphoproteomic and kinase activation profile when compared with adjacent mucosa. Integrated analysis reveals partial epithelial-mesenchymal transition, cytoskeletal remodeling, and transcriptional amplification as key drivers of polyp growth. Polarity and checkpoint signaling consistent with protective stress adaptation are conserved in non-polyp mucosa. This study is the first phosphoproteomic description of pediatric Peutz-Jeghers syndrome, identifying potential kinase biomarkers and therapeutic targets that could reduce the need for repeated invasive procedures in affected children.
2026-04-06 | Severe Iron Deficiency Anemia in a Jehovah's Witness diagnosed with Peutz-Jeghers Syndrome.
A 29-year-old woman presented with abdominal pain, nausea, vomiting, and non-bloody diarrhea and was found to have profound microcytic iron deficiency anemia (hemoglobin 4.8 g/dL). Endoscopy and colonoscopy revealed numerous colonic, rectal, and gastric polyps. CT enterography showed multiple large jejunal polyps and a short-segment intussusception without obstruction. Histopathology confirmed hamartomatous polyps, and genetic testing identified a heterozygous pathogenic Serine/threonine kinase 11 (STK11/LKB1) variant, confirming Peutz-Jeghers syndrome. As a Jehovah's Witness, she declined allogenic blood products. A comprehensive transfusion-free anemia management protocol, including intravenous iron dextran, erythropoiesis-stimulating agents, vitamin supplementation, and minimization of iatrogenic blood loss, resulted in hemoglobin to improve to 10.9 g/dL at 4 weeks and 14.0 g/dL at 4 months, enabling elective robotic-assisted jejunal polypectomy. This case highlights Peutz-Jeghers syndrome as an uncommon cause of severe iron deficiency anemia and illustrates a multidisciplinary, ethically sensitive, transfusion-sparing approach to managing life-threatening anemia in a Jehovah's Witness patient.
proteins
2026-06-30 | Pyloric botulinum toxin injection and single-port laparoscopic intragastric surgery for bulbus hamartoma.
Gastrointestinal polyps are associated with risks such as bleeding, intussusception, obstruction and malignancy, necessitating removal. Technological advancements in endoscopic and laparoscopic surgery have introduced minimally invasive options like laparoscopic intragastric surgery (LIGS), especially beneficial for polyps that cannot be resected endoscopically. This report presents a 37-year-old male patient with Peutz-Jeghers Syndrome who exhibited symptoms of nausea, vomiting and weight loss. Endoscopy and computed tomography imaging revealed obstructive polyps in the bulbus and gastric cardia. The patient underwent single-port LIGS with preoperative botulinum toxin injection to facilitate pyloric opening. This combined approach allowed effective lesion resection without requiring extensive gastric resection. Pathology confirmed a hamartomatous polyp in the bulbus and high-grade dysplasia with negative margin in the gastric cardia. LIGS, particularly with botulinum toxin assistance, appears to be a safe and effective method for excising intraluminal lesions in complex anatomical areas, such as the duodenal bulbus and cardia.
2025-06-22 | Truncated LKB1 nonenzymatically enhances Fas-induced apoptosis by acting as a surrogate of Smac.
Although liver kinase B1 (LKB1) has been established as a tumor suppressor kinase, its mechanism of action is incompletely understood. Here we describe a novel nonenzymatic function of LKB1 in cell death induced by Fas/CD95. In BID knockout HeLa cells, inactivation of mitochondrial outer membrane permeabilization (MOMP) prevents Smac-induced inhibition of X-linked inhibitor of apoptosis (XIAP), causing resistance to Fas-induced apoptosis. However, reexpression of LKB1 in those cells naturally deficient for endogenous LKB1 restored apoptosis. Mechanistically, caspase-8 activated by Fas processed LKB1 to a truncated form, tLKB1. Both WT and kinase-inactive LKB1 antagonized XIAP to restore apoptosis, but somatic mutants of LKB1 found in Peutz-Jeghers syndrome (PJS) failed to do so. Thus, in addition to the known caspase-8 / tBid / Smac / XIAP pro-apoptotic axis, our results unveil a novel one, caspase-8 / tLKB1 / XIAP that potentially contributes to the antitumor functions of LKB1.
2007-10-02 | Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction.
Germline mutations of the serine/threonine kinase LKB1 (also known as STK11) lead to Peutz-Jeghers syndrome (PJS) that is associated with increased incidence of malignant cancers. However, the tumor suppressor function of LKB1 has not been fully elucidated. We applied yeast two-hybrid screening and identified that a novel WD-repeat protein WDR6 was able to interact with LKB1. Immunofluorescence staining revealed that WDR6 was localized in cytoplasm, similar to the localization of LKB1. Expression of LKB1 was able to inhibit colony formation of Hela cells. Interestingly, coexpression of WDR6 with LKB1 enhanced the inhibitory effect of LKB1 on Hela cell proliferation. Consistently, WDR6 was able to synergize with LKB1 in cell cycle G1 arrest in Hela cells. Coexpression of WDR6 and LKB1 was able to induce a cyclin-dependent kinase (CDK) inhibitor p27(Kip1). Furthermore, the stimulatory effect of LKB1 on p27(Kip1) promoter activity was significantly elevated by coexpression with WDR6. Collectively, these results provided initial evidence that WDR6 is implicated in the cell growth inhibitory pathway of LKB1 via regulation of p27(Kip1).
2003-11-24 | MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm.
Mutations in the LKB1 protein kinase result in the inherited Peutz Jeghers cancer syndrome. LKB1 has been implicated in regulating cell proliferation and polarity although little is known about how this enzyme is regulated. We recently showed that LKB1 is activated through its interaction with STRADalpha, a catalytically deficient pseudokinase. Here we show that endogenous LKB1-STRADalpha complex is associated with a protein of unknown function, termed MO25alpha, through the interaction of MO25alpha with the last three residues of STRADalpha. MO25alpha and STRADalpha anchor LKB1 in the cytoplasm, excluding it from the nucleus. Moreover, MO25alpha enhances the formation of the LKB1-STRADalpha complex in vivo, stimulating the catalytic activity of LKB1 approximately 10-fold. We demonstrate that the related STRADbeta and MO25beta isoforms are also able to stabilize LKB1 in an active complex and that it is possible to isolate complexes of LKB1 bound to STRAD and MO25 isoforms, in which the subunits are present in equimolar amounts. Our results indicate that MO25 may function as a scaffolding component of the LKB1-STRAD complex and plays a crucial role in regulating LKB1 activity and cellular localization.
2002-06-15 | Growth arrest by the LKB1 tumor suppressor: induction of p21WAF1/CIP1
Germline mutations of the LKB1 tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS), with a predisposition to cancer. LKB1 encodes for a nuclear and cytoplasmic serine/threonine kinase, which is inactivated by mutations observed in PJS patients. Restoring LKB1 activity into cancer cell lines defective for its expression results in a G(1) cell cycle arrest. Here we have investigated molecular mechanisms leading to this arrest. Reintroduced active LKB1 was cytoplasmic and nuclear, whereas most kinase-defective PJS mutants of LKB1 localized predominantly to the nucleus. Moreover, when LKB1 was forced to remain cytoplasmic through disruption of the nuclear localization signal, it retained full growth suppression activity in a kinase-dependent manner. LKB1-mediated G(1) arrest was found to be bypassed by co-expression of the G(1) cyclins cyclin D1 and cyclin E. In addition, the protein levels of the CDK inhibitor p21(WAF1/CIP1) and p21 promoter activity were specifically upregulated in LKB1-transfected cells. Both the growth arrest and the induction of the p21 promoter were found to be p53-dependent. These results suggest that growth suppression by LKB1 is mediated through signaling of cytoplasmic LKB1 to induce p21 through a p53-dependent mechanism.
gene therapies
2026-09-28 | Integrated Transcriptomic Analysis Reveals Distinct Molecular and Immune Microenvironment Features of Peutz–Jeghers Syndrome-Associated Lobular Endocervical Glandular Hyperplasia and Gastric-Type Endocervical Adenocarcinoma
Background: Gastric-type endocervical adenocarcinoma (GAS) is an aggressive, human papillomavirus-independent cervical adenocarcinoma, whereas lobular endocervical glandular hyperplasia (LEGH) is considered a potential precursor. Molecular and immune microenvironment differences between Peutz–Jeghers syndrome-associated LEGH (PJS-LEGH) and GAS (PJS-GAS) remain poorly characterized. This study aimed to characterize these differences through integrated transcriptomic analysis. Methods: Bulk RNA sequencing was performed on tissues from 7 PJS-LEGH and 8 PJS-GAS cases. Differential expression and functional enrichment analyses were integrated with weighted gene co-expression network analysis (WGCNA), molecular interaction network analysis, and machine learning. Immune-related transcriptional patterns were assessed using single-sample gene set enrichment analysis (ssGSEA) and xCell, with CD45/CD4 multiplex immunofluorescence for preliminary tissue-level assessment. Results: We identified 1794 differentially expressed genes, including 976 upregulated and 818 downregulated genes in PJS-GAS. Functional and network analyses highlighted differences involving ciliary biology, epithelial differentiation, chemokine signaling, and immune regulation. ssGSEA revealed higher scores for selected T-cell, dendritic-cell, monocyte, and myeloid-derived suppressor cell signatures in PJS-GAS. xCell provided complementary evidence of higher scores for selected immune-cell populations, together with activation- and inhibition-associated transcriptional signatures. Integrated analyses converged on PTPRC, encoding the pan-leukocyte marker CD45, as a prominent leukocyte-associated feature of PJS-GAS. Multiplex immunofluorescence showed higher CD45+ and CD4+ cell densities in the sampled PJS-GAS tissues. Conclusions: This study provides the first transcriptomic comparison of PJS-LEGH and PJS-GAS and identifies distinct molecular features and increased immune-cell-associated transcriptional signatures with coexisting activation- and inhibition-associated expression patterns in PJS-GAS.
2026-09-23 | Presumed Intraductal Papillary Mucinous Neoplasms in Individuals at High Risk for Pancreatic Cancer.
Pancreatic cystic lesions are common during surveillance of individuals at hereditary risk for pancreatic cancer, but whether their incidence and progression differ across genetic risk groups remains uncertain. To compare the incidence, morphologic characteristics, and progression of presumed intraductal papillary mucinous neoplasms (IPMNs) in individuals at high risk of PC across hereditary risk groups. This multicenter cohort study was conducted from January 2016 to December 2025 at 25 centers participating in the Italian Registry of Families at Risk of Pancreatic Cancer. Participants were individuals undergoing pancreatic surveillance with magnetic resonance imaging with cholangiopancreatography and/or endoscopic ultrasonography. Familial pancreatic cancer without pathogenic germline variants vs pathogenic germline variant (PGV) carrier status, further grouped into 3 predefined categories: PGV1 (Peutz-Jeghers syndrome or CDKN2A sequence variant carriers), PGV2 (BRCA2 or ATM variant carriers), and PGV3 (Lynch syndrome-associated genes or BRCA1 or PALB2 variant carriers). Cumulative incidence of presumed IPMNs, longitudinal changes in index cyst diameter and main pancreatic duct diameter, and progression to worrisome features or high-risk stigmata. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) for incident IPMNs, adjusted for hereditary risk, age, sex, body mass index, tobacco smoking status, and diabetes. Among 1688 high-risk individuals (median age, 56 years [IQR, 50-64 years]; 1055 women [62.5%]), 496 (29.4%) had a presumed IPMN. Median follow-up from enrollment was 17 months (IQR, 0-36 months). A total of 1298 participants (76.9%) did not have a presumed pancreatic cyst at baseline, and 124 (9.6%) of these participants developed an incident lesion during follow-up. In the complete-case multivariable analysis of 1245 participants and 123 events, PGV1 (adjusted HR [AHR], 1.82; 95% CI, 0.97-3.43), PGV2 (AHR, 0.81; 95% CI, 0.45-1.45), and PGV3 (AHR, 0.70; 95% CI, 0.34-1.44) were not associated with incident cyst development compared with FPC, whereas older age was associated with higher incidence (AHR per year, 1.04; 95% CI, 1.02-1.05). Longitudinal trajectories of cyst growth (time × group interaction: χ2 = 14.4; df = 15; P = .49) and main pancreatic duct diameter (time × group interaction: χ2 = 4.35; df = 15; P > .99) did not differ significantly across groups, and progression to worrisome features or high-risk stigmata was infrequent (13 patients [2.6%]). In this multicenter cohort study of individuals at high risk of PC who were undergoing pancreatic surveillance, the incidence and short-term progression of presumed IPMNs did not differ significantly across hereditary risk groups, whereas older age was associated with incident cyst development. Longer follow-up appears to be needed to assess potential gene-specific differences.
2026-07-13 | Clinical and genetic features of pediatric hereditary polyposis syndromes in Israel: A nationwide multicenter cohort.
Hereditary polyposis syndromes in children are rare, heterogeneous disorders associated with significant morbidity and long-term risk of malignancy. Current data on their presentation, management, and outcomes in pediatric populations remain limited. We conducted a nationwide, multicenter, retrospective study that included children diagnosed with polyposis syndromes in eight pediatric gastroenterology centers in Israel. Demographic, genetic, clinical, endoscopic, and outcome data were collected. A total of 105 children were included: 30 with juvenile polyposis syndrome (JPS), 26 with familial adenomatous polyposis (FAP), 19 with Peutz-Jeghers syndrome, 16 with phosphatase and tensin homolog-hamartoma tumor syndrome, 8 with constitutional mismatch repair deficiency syndrome, 5 with hereditary mixed polyposis syndrome, and 1 with Lynch syndrome. The median age at diagnosis was 8 years (interquartile range 4.1-11.5). Overall, 43 (41%) were of Ashkenazi Jewish origin, and a family history of polyposis was present in 54 (51%). Genetic testing was performed in 91 (87%), identifying pathogenic variants in 77 (73%) of them. Gastrointestinal symptoms were reported in 60 (57%) and extra-intestinal manifestations in 48 (46%). Polyposis-related surgery was required in 22 (21%) children. Malignancy in eight children included two cases of colorectal carcinoma and glioblastoma multiforme, T cell lymphoma with Wilm's tumor, medulloblastoma, ganglioneuroblastoma, and abdominal adenocarcinoma. Three mortality events were recorded. Israeli children with hereditary polyposis syndromes present with diverse clinical and genetic features. Despite increasing use of genetic testing, morbidity and malignancy risks remain substantial, highlighting the need for early recognition, surveillance, and multidisciplinary care.
2026-05-14 | Acute intestinal intussusception revealing Peutz-Jeghers Syndrome in a 16-year-old male: a case report.
Peutz-Jeghers Syndrome (PJS) is a rare autosomal dominant disorder characterized by hamartomatous polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. Patients are at high risk for complications such as bleeding, obstruction, and especially small-bowel intussusception, which often occurs in childhood or adolescence. Early recognition is essential, as intussusception can be the first life-threatening presentation of PJS. This case highlights the importance of considering PJS in young patients presenting with acute intestinal obstruction. A 16-year-old male with no medical history presented with 48 hours of diffuse abdominal pain, vomiting, cessation of feces and flatus, and melena. Examination showed generalized abdominal guarding and a palpable left-flank mass. Laboratory tests revealed leukocytosis, elevated CRP, metabolic acidosis, and high lactate. CT scan demonstrated a jejuno-jejunal intussusception with suspected distal ileal intussusceptions. Emergency laparotomy revealed a 2-meter gangrenous jejuno-jejunal intussusception and two additional ileal invaginations caused by polypoid lesions. A segmental small-bowel resection with primary anastomosis and enterotomy for polyp removal was performed. Histology confirmed multiple hamartomatous polyps consistent with PJS. The postoperative course was favorable, and the patient was referred for genetic counseling and surveillance. PJS often presents with gastrointestinal polyps that can act as lead points for intussusception. Up to 69% of patients experience at least one episode, particularly in adolescence. Multiple synchronous intussusceptions, as in this case, require thorough intraoperative evaluation of the entire small bowel to identify additional polyps and prevent recurrence. While bowel preservation through reduction and polypectomy is preferred, extensive resection may be necessary when ischemia or necrosis is present. Long-term management includes routine endoscopic surveillance, removal of polyps ≥15 mm, and monitoring for the significantly elevated lifetime risk of gastrointestinal and extra-intestinal malignancies. Genetic counseling is critical for confirming STK11 mutations and informing family screening. This case demonstrates that PJS may initially present as severe, multifocal small-bowel intussusception in adolescents. Prompt diagnosis, surgical management, and comprehensive evaluation for additional polyps are essential to prevent recurrence and complications. Long-term multidisciplinary follow-up is vital due to the high risk of malignancy and recurrence inherent to PJS.
2026-03-28 | Genetic Predisposition to Pancreatic Cancer: A Systematic Review of Hereditary Syndromes and Familial Aggregation.
Pancreatic cancer is a highly lethal malignancy, with a 5-year survival rate of approximately 8%. Roughly 10% of cases occur in individuals with familial pancreatic cancer or identified high-risk germline mutations, including STK11, CDKN2A, BRCA1/2, MLH1, and MSH2. We aimed to evaluate the risk of pancreatic cancer associated with inherited genetic mutations and to characterize these genetic syndromes. A systematic search of the PubMed database up to 2024 identified 1500 articles, of which 90 met the criteria for inclusion in this review. High-risk individuals were defined as those with at least a 10-fold increased risk, moderate risk as 5-10-fold and low risk as under 5-fold. High-risk individuals included those with Peutz-Jeghers syndrome (132-140-fold risk), hereditary pancreatitis (50-87-fold risk), Familial Atypical Multiple Mole Melanoma syndrome (up to 48-fold risk), hereditary breast and ovarian cancer with BRCA2 mutation (up to 22-fold risk), and familial pancreatic cancer with at least three affected relatives (up to 32-fold risk). Moderate-risk patients had BRCA1, MLH1, MSH2, MSH6, p53, and ATM mutations, as well as familial pancreatic cancer with 1-2 affected kindred. Low-risk patients had familial adenomatous polyposis. Identifying high-risk individuals is crucial for effective genetic counseling, testing, and potential screening programs to facilitate early diagnosis and improve outcomes. Future research should prioritize large prospective cohorts, screening programs, and the integration of emerging technologies, such as AI-assisted imaging.
antibodies
2026-08-19 | Fibroblast heterogeneity in Peutz-Jeghers syndrome: identifying the polyp-driving subset†.
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder caused by germline mutations in STK11, and is characterized by gastrointestinal hamartomatous polyps, the recurrent development of which significantly impacts patients' quality of life. While stromal cells have been implicated in PJS polyp formation, their specific characteristics remain unclear. Domènech-Moreno et al identify polyp-enriched crypt top fibroblasts (pCTFs) as the pathogenic fibroblast population and demonstrate that interleukin (IL)-11, a major secretory factor produced by these cells, serves as a critical mediator linking STK11 deficiency to epithelial proliferation. The study reveals that Stk11 loss triggers IL-11 expression, which in turn reinforces the pathogenic pCTF phenotype through autocrine signaling, forming a feedforward loop. Importantly, IL-11 neutralization significantly reduces polyp formation in a faithful mouse model, providing strong preclinical evidence for therapeutic translation. This work represents a significant advance in our understanding of PJS pathogenesis and establishes IL-11 as a promising therapeutic target. Future investigations into the effects of IL-11 neutralization on established polyps will further refine the translational potential of these findings for preventive intervention strategies. © 2026 The Pathological Society of Great Britain and Ireland.
2026-01-23 | A novel effect of bevacizumab in reducing characteristic pigmentation in Peutz-Jeghers syndrome: a case report and literature review.
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation (e.g., perioral melanotic macules) and gastrointestinal hamartomatous polyps, with heightened cancer susceptibility. This report describes a 34-year-old Han Chinese ethnicity woman with familial Peutz-Jeghers syndrome (PJS) and stage IIA HPV-independent gastric-type endocervical adenocarcinoma following bevacizumab therapy. Initial concurrent chemoradiation (paclitaxel with either nedaplatin or cisplatin with volumetric modulated arc therapy) achieved partial response, while subsequent maintenance therapy combining bevacizumab with chemotherapy induced complete radiographic remission. Crucially, progressive fading of pathognomonic perioral melanotic macules demonstrated temporal correlation with bevacizumab administration, with sustained remission at 1-year follow-up. These findings challenge the conventional paradigm of PJS pigmentation as a static feature by demonstrating that VEGF-mediated angiogenesis concurrently drives carcinogenesis and melanin deposition. The case highlights three key implications, namely: (1) validation of bevacizumab's dual therapeutic potential against PJS-associated malignancies and cutaneous manifestations, (2) proposal of mucocutaneous pigmentation as a dynamic biomarker for treatment response monitoring, and (3) urgent need for prospective clinical trials evaluating VEGF inhibition in PJS through longitudinal surveillance of oncologic control and pigment dynamics.
2025-06-20 | IL-17 links the tumor suppressor LKB1 to gastrointestinal inflammation and polyposis.
Mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of gastrointestinal (GI) polyps of unknown etiology. Here, we identify IL-17 as a novel driver of LKB1-dependent polyp growth. GI tumors from mice bearing heterozygous mutations in Stk11 (which encodes LKB1) display signatures of pathogenic IL-17-producing CD4+ T helper 17 (TH17) cells. LKB1 constrains T cell inflammatory potential, as Stk11/LKB1 haploinsufficiency promotes T cell differentiation toward pathogenic IL-17-producing T cell lineages (CD4+ TH17 and CD8+ Tc17) in vitro and following intestinal infection. Mechanistically, aberrant CREB-regulated transcription coactivator 2 (CRTC2)-dependent signaling drives pathogenic TH17 cell programs downstream of LKB1 haploinsufficiency. Targeting this circuit via CRTC2 deletion or IL-17 blockade antagonizes GI polyp growth in mouse models of Peutz-Jeghers syndrome. These findings establish LKB1 as a gatekeeper of inflammatory type 3 (IL-17-dependent) T cell responses and identify a CRTC2-IL-17 signaling axis that can be targeted therapeutically to block the growth of LKB1 mutant GI tumors.
2025-03-12 | Interleukin-11 expressed in the polyp-enriched fibroblast subset is a potential therapeutic target in Peutz-Jeghers syndrome.
Peutz-Jeghers syndrome (PJS) is associated with early-onset gastrointestinal polyposis caused by hereditary inactivating pathogenic variants in the tumor suppressor gene STK11 (LKB1). Due to lack of prophylactic therapies, management of PJS polyps requires frequent surveillance. Interestingly, studies in mouse models have revealed that stromal cells drive the polyp formation, but detailed understanding of the cell types and interactions involved has been lacking. Using single-cell RNA sequencing of PJS mouse model polyps, we here identify a polyp-enriched crypt top fibroblast (pCTF) cluster characterized by a transcriptional signature also enriched in PJS patient polyps. The pCTF signature was also noted in primary fibroblasts in vitro following acute STK11 loss. Targeted deletion of Stk11 in crypt top fibroblasts using Foxl1-Cre led to upregulation of the pCTF signature genes and later to polyposis. pCTFs displayed similarity to inflammation-associated fibroblasts, and polyposis was exacerbated by inflammation. Cell-cell communication analysis identified interleukin 11 (IL-11) as a potential pCTF inducer, and consistent with this, IL-11 was required for fibroblast reprogramming toward pCTFs following STK11 loss. Importantly, a neutralizing IL-11 antibody efficiently reduced polyp formation in a PJS model indicating a key, targetable role for IL-11 in polyp development. Together the results characterize pCTFs as a PJS polyp-enriched fibroblast subset and identify IL-11 as a key mediator of fibroblast reprogramming and a potential therapeutic target in PJS. © 2025 The Pathological Society of Great Britain and Ireland.
2025-02-28 | Gastric-type endocervical adenocarcinoma, superficial myofibroblastoma, sex cord-stromal tumors, and HSIL in Peutz-Jeghers syndrome: a rare case report, genetic characterization, and review of literature.
Peutz-Jeghers syndrome (PJS) is characterized by an increased risk of gynecologic tumors. Gastric-type endocervical adenocarcinoma (GEA) is a rare non-human papillomavirus (HPV)-related tumor. We reported an uncommon case of a 39-year-old woman with PJS who developed GEA, superficial cervical vaginal myofibroblastoma, sex cord-stromal tumors with annular tubules of the ovaries, and cervical and vaginal high-grade squamous interepithelial neoplasia (HSIL). Before being verified GEA, the patient had been experiencing suspicious symptoms for over 9 years, with nabothian cysts and vaginitis being misdiagnosed. HSIL displayed widespread p16 immunostaining, and HPV DNA screening confirmed HPV-18 infection, although GEA was negative. Further, we verified TP53 mutation and HER2 amplification of GEA by fluorescence in situ hybridization (FISH). TP53 was the most commonly mutated gene. The therapy with the anti-HER2 antibody trastuzumab was suggested based on HER2 amplification. We also analyzed the somatic mutations of GEA by whole genome sequencing (WES). There were 157 single nucleotide variations (SNVs) and 215 indels, with all of them being heterozygotes. Nonsynonymous and frameshift insertions were the most common kinds of mutations. The germine STK11 gene mutation was found, which may play an important role in tumor development. According to gene function enrichment analyses, the genomic changes primarily implicated general transcription or expression pathways and cell cycle pathways. In addition, the JAK2/STAT3 pathway could be a major focus of targeted therapy for GEA patients with PJS. Our findings show that the patient with PJS can have a variety of unusual gynecologic tumors. Patients with PJS must have routine gynecological, ultrasonographic, and cytological examinations to detect precursor or early-stage lesions. The patient's abnormal symptoms must be treated early with caution. A comprehensive genomic study reveals the potential causative genetic factors, therapeutic targets, and chemotherapy resistance of GEA. Further research will focus on the main driving genes, molecular mechanisms, and molecular target therapy in more patients.
other
2026-02-23 | Ischemic polypectomy for small-bowel polyps in pediatric Peutz-Jeghers syndrome.
Peutz-Jeghers syndrome (PJS) is characterized by the development of hamartomatous polyps in the gastrointestinal tract that can cause chronic blood loss. Ischemic polypectomy has emerged as a low-risk technique in adult patients with PJS but remains largely undocumented in pediatric populations. This video presents the first published case demonstrating ischemic polypectomy in a pediatric patient, to our knowledge. A 12-year-old girl with PJS and chronic anemia underwent balloon-assisted enteroscopy. Seven pedunculated small-bowel polyps were identified and treated using ischemic polypectomy with a detachable snare. Three representative polypectomies are shown. The snare was tightened at the polyp stalk until ischemic changes occurred, then cinched and deployed. One instance required a second snare because of equipment malfunction. All polyps were successfully treated without electrocautery, bleeding, or perforation. Follow-up demonstrated improvement in longstanding anemia, with a rise in hemoglobin from 9.1 to 12.4 g/dL at 6 weeks, supporting therapeutic benefit. Repeat capsule endoscopy was planned. Ischemic polypectomy using balloon-assisted enteroscopy is feasible, effective, and safe in pediatric PJS. By avoiding thermal energy, it may reduce the risk of transmural injury and represents a valuable option for children with numerous pedunculated small-bowel polyps.
2022-02-21 | RETRACTED ARTICLE: Multidisciplinary management for Peutz–Jeghers syndrome and prevention of vertical transmission to offspring using preimplantation genetic testing
Peutz Jeghers syndrome (PJS) is an autosomal dominant genetic disorder caused by STK11 mutation with a predisposition to gastrointestinal polyposis and cancer. PJS patients suffer poor quality of life and are highly concerned about whether deleterious mutations transmit to their offspring. Therefore, this study aimed to propose feasible clinical management and provide effective preimplantation genetic testing for monogenic defect (PGT-M) strategies to protect offspring from inheriting the disease.A hospital-based clinical retrospective analysis reviewing the clinical characteristics and fertility aspects was first conducted on 51 PJS patients at the First Affiliated Hospital of Zhengzhou University between January 2016 and March 2021. Among the 51 patients, the PGT-M strategy was further carried out in 4 couples, which started with a biopsy of the trophectoderm cells of embryos and whole genome amplification using multiple displacement amplification. Thereafter, single nucleotide polymorphism linkage analyses based on karyomapping were performed with copy number variations of the embryos identified simultaneously. Finally, prenatal diagnosis was used to verify the validity of the PGT-M results.A comprehensive management flowchart adopted by the multidisciplinary team model was formulated mainly focusing on clinical genetic and gastrointestinal aspects. Under the guidelines of this management, 32 embryos from 4 PJS pedigrees were diagnosed and 2 couples successfully conceived healthy babies free of the STK11 pathogenic mutation.Our comprehensive management could help affected families avoid having children with PJS through preimplantation genetic testing and provide meaningful guidance for multidisciplinary clinical practice on PJS.
2013-09-02 | LKB1 mutant in a KRAS activated adenocarcinoma of the lung associated with Peutz–Jeghers syndrome: A case report
We present a case of a 54-year-old woman who was diagnosed with a KRAS positive adenocarcinoma of the lung on the basis of a Peutz-Jeghers syndrome (PJS), which was unknown before. PJS is a rare hereditary disease, which may be associated with the development of poor outcome adenocarcinomas and LKB1-gene mutations. A very rare type of a LKB1 mutation was found, not previously described in lung cancer. Although seldom screened for LKB-1 mutations are found in up to 30% of lung adenocarcinomas and may be druggable therapeutic targets, in particular in KRAS mutant tumours in the near future as recent preclinical results with nucleotides demonstrate.
small molecules
2026-09-15 | STK11/LKB1 Loss in Cancer: From Developmental Constraint to Stress-Adapted Malignancy.
Peutz-Jeghers syndrome (PJS) presents an apparent biological paradox: heterozygous germline pathogenic variants in STK11 predispose to predominantly benign hamartomatous growth while conferring a markedly elevated lifetime risk of cancer, whereas somatic STK11 inactivation in established tumors is frequently associated with aggressive progression and therapeutic resistance. STK11 encodes liver kinase B1 (LKB1), a serine/threonine kinase that integrates metabolic, oxidative, architectural, and immune stress responses. Rather than acting solely as a direct brake on proliferation, LKB1 couples cellular growth, survival, and tissue organization to environmental fitness. We therefore propose a context-dependent stress adaptation framework in which impairment of STK11/LKB1 signaling relaxes stress-imposed constraints on cellular fitness, while the ultimate biological outcome is determined by allelic status, tissue context, and cooperating genetic alterations. In PJS, a heterozygous germline STK11 pathogenic variant creates a constitutional cancer predisposed state in which one functional allele is initially retained, although subsequent loss or impairment of the remaining allele may occur during tumor evolution. In sporadic cancers, somatic STK11 inactivation is often biallelic and frequently cooperates with alterations in KRAS, KEAP1, TP53, NF1, or PI3K-pathway genes. These genetic contexts can promote metabolic reprogramming, redox adaptation, autophagy dependence, immune exclusion, cellular plasticity, and therapeutic resistance, with the strongest mechanistic and clinical evidence currently derived from lung adenocarcinoma (LUAD). Within this framework, enhanced persistence under metabolic, oxidative, immune, and therapy-induced stress does not exclude proliferative effects of STK11 loss but provides a permissive background upon which cooperating oncogenic programs can drive clonal expansion and malignant progression. Stress adaptation creates dependencies on interconnected buffering systems, including antioxidant defenses, autophagy, metabolic plasticity, and ferroptosis suppression. Therapeutic strategies that simultaneously disrupt multiple compensatory pathways may therefore exceed tumor adaptive capacity, convert stress tolerance into therapeutic vulnerability, and provide a rational framework for treating LKB1-deficient tumors and other stress-adapted cancers.
2026-06-22 | Distinct mucosa-associated microbiota signatures and dysbiosis in Peutz-Jeghers syndrome polyps versus paired normal mucosa
Background Peutz-Jeghers syndrome (PJS) is an STK11/LKB1 -mutated autosomal dominant disorder with gastrointestinal hamartomatous polyps and elevated cancer risk, but the role of mucosa-associated microbiota in PJS polyp pathogenesis remains unclear. Aim To investigate the mucosal microbial signatures, dysbiosis characteristics, and potential biomarkers in PJS polyps versus paired normal small intestinal mucosa. Methods A paired-sample design was adopted, enrolling 44 genetically confirmed PJS patients. Mucosa-associated microbiota was profiled via 5R 16S rRNA gene sequencing. Statistical analyses included Wilcoxon rank-sum test, ANOSIM, Spearman’s correlation, and random forest modeling. Results Alpha diversity (Observed species, Chao1, Shannon) was markedly reduced in polyps (all P < 0.001), while Simpson index increased (P < 0.001). Beta diversity differed significantly between groups (ANOSIM, R = 0.0667, P = 0.002). Polyps were enriched in Pseudomonadota (70.00% vs. 49.51%, P < 0.001) and depleted in Bacillota , Bacteroidota (both P < 0.001). Microbial dysbiosis index (MDI) was higher in polyps (P < 0.001). A 9-genera random forest model achieved AUC = 0.897. Escherichia-Shigella correlated with polyp number (P < 0.05), and Enterococcus correlated with CA72–4 levels (P < 0.05). Conclusion PJS polyps exhibit significant mucosal microbial dysbiosis, which may serve as potential biomarkers and therapeutic targets for PJS.
2026-05-25 | Adrenocortical Carcinoma in Peutz-Jeghers Syndrome With a Rare STK11 Pathogenic Germline Variant: A Case Report.
Peutz-Jeghers syndrome (PJS) is an inherited, autosomal-dominant condition, featuring STK11 germline mutations, characterized by hamartomatous gastrointestinal polyps and increased cancer risk. The most commonly associated malignancies are gastrointestinal, pancreatic, and breast cancers. Herein, we report an extremely rare case of PJS with adrenocortical carcinoma (ACC). A 40-year-old woman was referred to University of Tsukuba Hospital with uncontrolled diabetes mellitus (DM) and hypokalemia in July 2021. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a 12 cm mass in the right adrenal gland and aortocaval lymph node swelling. Mucocutaneous hyperpigmentation in her lips and fingertips was observed, and multiple stomach and small intestine polyps were visible on CT. We performed open right adrenalectomy with right nephrectomy, partial hepatectomy, and aortocaval lymph node dissection before diagnosing ACC with lymph node metastasis from the pathology. After surgery, multiple lung and liver metastases developed, and combination chemotherapy (etoposide, doxorubicin, and cisplatin, plus mitotane) was started, achieving stable disease for 2 years. We also performed an OncoGuide NCC Oncopanel on the adrenal tumor specimen and blood sample, revealing a rarely reported pathogenic germline variant (c.394T>C, p.C132R) in STK11. This variant was registered as Likely Pathogenic in the NIH Clinvar public database, which led to a PJS diagnosis. This is the second report of ACC associated PJS in a rare germline variant of STK11. Although rare, loss of STK11 function may lead to cancers outside expected sites in PJS cases.
2026-05-05 | Phosphoproteomic and kinase networks reveal partial EMT and stress-adaptive growth programs in pediatric Peutz-Jeghers polyps.
Peutz-Jeghers syndrome (PJS) is a rare inherited cancer predisposing disorder associated with pathogenic variants of the Serine Threonine Kinase11 (STK11 / LKB1). Morbidity in children is driven by small intestinal obstruction from polyps. The molecular mechanisms driving polyp initiation and growth are poorly understood. We hypothesized that integrated phosphoproteomic analysis of pediatric Peutz-Jeghers polyps would reveal signaling networks driving polyp growth. Intestinal polyp and adjacent non-polyp mucosa from pediatric PJS patients undergoing therapeutic endoscopy-polypectomy underwent mass spectrometry-based proteomic and phosphoproteomic profiling. A bioinformatic pipeline and network analyses were performed to identify differential kinase activity, phosphopeptide enrichment, and signaling nodes relevant to polyp growth. Polyp tissue was enriched for proliferative signaling and biosynthetic drivers, including CLK1 and PKCβ, MAPK10, and MAPK11. Non-polyp mucosa however, exhibited higher expression of regulatory kinases such as HIPK2, PLK2, LATS1, STK38, and PRKCZ/PRKCI, reinforcing apoptosis, polarity, and Wnt/mTOR restraint. Phosphoproteomic networks in polyps support a partial epithelial-mesenchymal transition phenotype, amplified transcription and translation, and a survival shift from BAD-14-3-3 signaling toward YAP/mTOR/NF-kB. PJS polyps display a unique proteomic and phosphoproteomic signature that critically distinguishes PJS from other polyposis syndromes potentially lessening repeated invasive interventions in affected children. Small intestinal pediatric Peutz-Jeghers polyps express a distinct phosphoproteomic and kinase activation profile when compared with adjacent mucosa. Integrated analysis reveals partial epithelial-mesenchymal transition, cytoskeletal remodeling, and transcriptional amplification as key drivers of polyp growth. Polarity and checkpoint signaling consistent with protective stress adaptation are conserved in non-polyp mucosa. This study is the first phosphoproteomic description of pediatric Peutz-Jeghers syndrome, identifying potential kinase biomarkers and therapeutic targets that could reduce the need for repeated invasive procedures in affected children.
2026-04-06 | Severe Iron Deficiency Anemia in a Jehovah's Witness diagnosed with Peutz-Jeghers Syndrome.
A 29-year-old woman presented with abdominal pain, nausea, vomiting, and non-bloody diarrhea and was found to have profound microcytic iron deficiency anemia (hemoglobin 4.8 g/dL). Endoscopy and colonoscopy revealed numerous colonic, rectal, and gastric polyps. CT enterography showed multiple large jejunal polyps and a short-segment intussusception without obstruction. Histopathology confirmed hamartomatous polyps, and genetic testing identified a heterozygous pathogenic Serine/threonine kinase 11 (STK11/LKB1) variant, confirming Peutz-Jeghers syndrome. As a Jehovah's Witness, she declined allogenic blood products. A comprehensive transfusion-free anemia management protocol, including intravenous iron dextran, erythropoiesis-stimulating agents, vitamin supplementation, and minimization of iatrogenic blood loss, resulted in hemoglobin to improve to 10.9 g/dL at 4 weeks and 14.0 g/dL at 4 months, enabling elective robotic-assisted jejunal polypectomy. This case highlights Peutz-Jeghers syndrome as an uncommon cause of severe iron deficiency anemia and illustrates a multidisciplinary, ethically sensitive, transfusion-sparing approach to managing life-threatening anemia in a Jehovah's Witness patient.
proteins
2026-06-30 | Pyloric botulinum toxin injection and single-port laparoscopic intragastric surgery for bulbus hamartoma.
Gastrointestinal polyps are associated with risks such as bleeding, intussusception, obstruction and malignancy, necessitating removal. Technological advancements in endoscopic and laparoscopic surgery have introduced minimally invasive options like laparoscopic intragastric surgery (LIGS), especially beneficial for polyps that cannot be resected endoscopically. This report presents a 37-year-old male patient with Peutz-Jeghers Syndrome who exhibited symptoms of nausea, vomiting and weight loss. Endoscopy and computed tomography imaging revealed obstructive polyps in the bulbus and gastric cardia. The patient underwent single-port LIGS with preoperative botulinum toxin injection to facilitate pyloric opening. This combined approach allowed effective lesion resection without requiring extensive gastric resection. Pathology confirmed a hamartomatous polyp in the bulbus and high-grade dysplasia with negative margin in the gastric cardia. LIGS, particularly with botulinum toxin assistance, appears to be a safe and effective method for excising intraluminal lesions in complex anatomical areas, such as the duodenal bulbus and cardia.
2025-06-22 | Truncated LKB1 nonenzymatically enhances Fas-induced apoptosis by acting as a surrogate of Smac.
Although liver kinase B1 (LKB1) has been established as a tumor suppressor kinase, its mechanism of action is incompletely understood. Here we describe a novel nonenzymatic function of LKB1 in cell death induced by Fas/CD95. In BID knockout HeLa cells, inactivation of mitochondrial outer membrane permeabilization (MOMP) prevents Smac-induced inhibition of X-linked inhibitor of apoptosis (XIAP), causing resistance to Fas-induced apoptosis. However, reexpression of LKB1 in those cells naturally deficient for endogenous LKB1 restored apoptosis. Mechanistically, caspase-8 activated by Fas processed LKB1 to a truncated form, tLKB1. Both WT and kinase-inactive LKB1 antagonized XIAP to restore apoptosis, but somatic mutants of LKB1 found in Peutz-Jeghers syndrome (PJS) failed to do so. Thus, in addition to the known caspase-8 / tBid / Smac / XIAP pro-apoptotic axis, our results unveil a novel one, caspase-8 / tLKB1 / XIAP that potentially contributes to the antitumor functions of LKB1.
2007-10-02 | Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction.
Germline mutations of the serine/threonine kinase LKB1 (also known as STK11) lead to Peutz-Jeghers syndrome (PJS) that is associated with increased incidence of malignant cancers. However, the tumor suppressor function of LKB1 has not been fully elucidated. We applied yeast two-hybrid screening and identified that a novel WD-repeat protein WDR6 was able to interact with LKB1. Immunofluorescence staining revealed that WDR6 was localized in cytoplasm, similar to the localization of LKB1. Expression of LKB1 was able to inhibit colony formation of Hela cells. Interestingly, coexpression of WDR6 with LKB1 enhanced the inhibitory effect of LKB1 on Hela cell proliferation. Consistently, WDR6 was able to synergize with LKB1 in cell cycle G1 arrest in Hela cells. Coexpression of WDR6 and LKB1 was able to induce a cyclin-dependent kinase (CDK) inhibitor p27(Kip1). Furthermore, the stimulatory effect of LKB1 on p27(Kip1) promoter activity was significantly elevated by coexpression with WDR6. Collectively, these results provided initial evidence that WDR6 is implicated in the cell growth inhibitory pathway of LKB1 via regulation of p27(Kip1).
2003-11-24 | MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm.
Mutations in the LKB1 protein kinase result in the inherited Peutz Jeghers cancer syndrome. LKB1 has been implicated in regulating cell proliferation and polarity although little is known about how this enzyme is regulated. We recently showed that LKB1 is activated through its interaction with STRADalpha, a catalytically deficient pseudokinase. Here we show that endogenous LKB1-STRADalpha complex is associated with a protein of unknown function, termed MO25alpha, through the interaction of MO25alpha with the last three residues of STRADalpha. MO25alpha and STRADalpha anchor LKB1 in the cytoplasm, excluding it from the nucleus. Moreover, MO25alpha enhances the formation of the LKB1-STRADalpha complex in vivo, stimulating the catalytic activity of LKB1 approximately 10-fold. We demonstrate that the related STRADbeta and MO25beta isoforms are also able to stabilize LKB1 in an active complex and that it is possible to isolate complexes of LKB1 bound to STRAD and MO25 isoforms, in which the subunits are present in equimolar amounts. Our results indicate that MO25 may function as a scaffolding component of the LKB1-STRAD complex and plays a crucial role in regulating LKB1 activity and cellular localization.
2002-06-15 | Growth arrest by the LKB1 tumor suppressor: induction of p21WAF1/CIP1
Germline mutations of the LKB1 tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS), with a predisposition to cancer. LKB1 encodes for a nuclear and cytoplasmic serine/threonine kinase, which is inactivated by mutations observed in PJS patients. Restoring LKB1 activity into cancer cell lines defective for its expression results in a G(1) cell cycle arrest. Here we have investigated molecular mechanisms leading to this arrest. Reintroduced active LKB1 was cytoplasmic and nuclear, whereas most kinase-defective PJS mutants of LKB1 localized predominantly to the nucleus. Moreover, when LKB1 was forced to remain cytoplasmic through disruption of the nuclear localization signal, it retained full growth suppression activity in a kinase-dependent manner. LKB1-mediated G(1) arrest was found to be bypassed by co-expression of the G(1) cyclins cyclin D1 and cyclin E. In addition, the protein levels of the CDK inhibitor p21(WAF1/CIP1) and p21 promoter activity were specifically upregulated in LKB1-transfected cells. Both the growth arrest and the induction of the p21 promoter were found to be p53-dependent. These results suggest that growth suppression by LKB1 is mediated through signaling of cytoplasmic LKB1 to induce p21 through a p53-dependent mechanism.
gene therapies
2026-09-28 | Integrated Transcriptomic Analysis Reveals Distinct Molecular and Immune Microenvironment Features of Peutz–Jeghers Syndrome-Associated Lobular Endocervical Glandular Hyperplasia and Gastric-Type Endocervical Adenocarcinoma
Background: Gastric-type endocervical adenocarcinoma (GAS) is an aggressive, human papillomavirus-independent cervical adenocarcinoma, whereas lobular endocervical glandular hyperplasia (LEGH) is considered a potential precursor. Molecular and immune microenvironment differences between Peutz–Jeghers syndrome-associated LEGH (PJS-LEGH) and GAS (PJS-GAS) remain poorly characterized. This study aimed to characterize these differences through integrated transcriptomic analysis. Methods: Bulk RNA sequencing was performed on tissues from 7 PJS-LEGH and 8 PJS-GAS cases. Differential expression and functional enrichment analyses were integrated with weighted gene co-expression network analysis (WGCNA), molecular interaction network analysis, and machine learning. Immune-related transcriptional patterns were assessed using single-sample gene set enrichment analysis (ssGSEA) and xCell, with CD45/CD4 multiplex immunofluorescence for preliminary tissue-level assessment. Results: We identified 1794 differentially expressed genes, including 976 upregulated and 818 downregulated genes in PJS-GAS. Functional and network analyses highlighted differences involving ciliary biology, epithelial differentiation, chemokine signaling, and immune regulation. ssGSEA revealed higher scores for selected T-cell, dendritic-cell, monocyte, and myeloid-derived suppressor cell signatures in PJS-GAS. xCell provided complementary evidence of higher scores for selected immune-cell populations, together with activation- and inhibition-associated transcriptional signatures. Integrated analyses converged on PTPRC, encoding the pan-leukocyte marker CD45, as a prominent leukocyte-associated feature of PJS-GAS. Multiplex immunofluorescence showed higher CD45+ and CD4+ cell densities in the sampled PJS-GAS tissues. Conclusions: This study provides the first transcriptomic comparison of PJS-LEGH and PJS-GAS and identifies distinct molecular features and increased immune-cell-associated transcriptional signatures with coexisting activation- and inhibition-associated expression patterns in PJS-GAS.
2026-09-23 | Presumed Intraductal Papillary Mucinous Neoplasms in Individuals at High Risk for Pancreatic Cancer.
Pancreatic cystic lesions are common during surveillance of individuals at hereditary risk for pancreatic cancer, but whether their incidence and progression differ across genetic risk groups remains uncertain. To compare the incidence, morphologic characteristics, and progression of presumed intraductal papillary mucinous neoplasms (IPMNs) in individuals at high risk of PC across hereditary risk groups. This multicenter cohort study was conducted from January 2016 to December 2025 at 25 centers participating in the Italian Registry of Families at Risk of Pancreatic Cancer. Participants were individuals undergoing pancreatic surveillance with magnetic resonance imaging with cholangiopancreatography and/or endoscopic ultrasonography. Familial pancreatic cancer without pathogenic germline variants vs pathogenic germline variant (PGV) carrier status, further grouped into 3 predefined categories: PGV1 (Peutz-Jeghers syndrome or CDKN2A sequence variant carriers), PGV2 (BRCA2 or ATM variant carriers), and PGV3 (Lynch syndrome-associated genes or BRCA1 or PALB2 variant carriers). Cumulative incidence of presumed IPMNs, longitudinal changes in index cyst diameter and main pancreatic duct diameter, and progression to worrisome features or high-risk stigmata. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) for incident IPMNs, adjusted for hereditary risk, age, sex, body mass index, tobacco smoking status, and diabetes. Among 1688 high-risk individuals (median age, 56 years [IQR, 50-64 years]; 1055 women [62.5%]), 496 (29.4%) had a presumed IPMN. Median follow-up from enrollment was 17 months (IQR, 0-36 months). A total of 1298 participants (76.9%) did not have a presumed pancreatic cyst at baseline, and 124 (9.6%) of these participants developed an incident lesion during follow-up. In the complete-case multivariable analysis of 1245 participants and 123 events, PGV1 (adjusted HR [AHR], 1.82; 95% CI, 0.97-3.43), PGV2 (AHR, 0.81; 95% CI, 0.45-1.45), and PGV3 (AHR, 0.70; 95% CI, 0.34-1.44) were not associated with incident cyst development compared with FPC, whereas older age was associated with higher incidence (AHR per year, 1.04; 95% CI, 1.02-1.05). Longitudinal trajectories of cyst growth (time × group interaction: χ2 = 14.4; df = 15; P = .49) and main pancreatic duct diameter (time × group interaction: χ2 = 4.35; df = 15; P > .99) did not differ significantly across groups, and progression to worrisome features or high-risk stigmata was infrequent (13 patients [2.6%]). In this multicenter cohort study of individuals at high risk of PC who were undergoing pancreatic surveillance, the incidence and short-term progression of presumed IPMNs did not differ significantly across hereditary risk groups, whereas older age was associated with incident cyst development. Longer follow-up appears to be needed to assess potential gene-specific differences.
2026-07-13 | Clinical and genetic features of pediatric hereditary polyposis syndromes in Israel: A nationwide multicenter cohort.
Hereditary polyposis syndromes in children are rare, heterogeneous disorders associated with significant morbidity and long-term risk of malignancy. Current data on their presentation, management, and outcomes in pediatric populations remain limited. We conducted a nationwide, multicenter, retrospective study that included children diagnosed with polyposis syndromes in eight pediatric gastroenterology centers in Israel. Demographic, genetic, clinical, endoscopic, and outcome data were collected. A total of 105 children were included: 30 with juvenile polyposis syndrome (JPS), 26 with familial adenomatous polyposis (FAP), 19 with Peutz-Jeghers syndrome, 16 with phosphatase and tensin homolog-hamartoma tumor syndrome, 8 with constitutional mismatch repair deficiency syndrome, 5 with hereditary mixed polyposis syndrome, and 1 with Lynch syndrome. The median age at diagnosis was 8 years (interquartile range 4.1-11.5). Overall, 43 (41%) were of Ashkenazi Jewish origin, and a family history of polyposis was present in 54 (51%). Genetic testing was performed in 91 (87%), identifying pathogenic variants in 77 (73%) of them. Gastrointestinal symptoms were reported in 60 (57%) and extra-intestinal manifestations in 48 (46%). Polyposis-related surgery was required in 22 (21%) children. Malignancy in eight children included two cases of colorectal carcinoma and glioblastoma multiforme, T cell lymphoma with Wilm's tumor, medulloblastoma, ganglioneuroblastoma, and abdominal adenocarcinoma. Three mortality events were recorded. Israeli children with hereditary polyposis syndromes present with diverse clinical and genetic features. Despite increasing use of genetic testing, morbidity and malignancy risks remain substantial, highlighting the need for early recognition, surveillance, and multidisciplinary care.
2026-05-14 | Acute intestinal intussusception revealing Peutz-Jeghers Syndrome in a 16-year-old male: a case report.
Peutz-Jeghers Syndrome (PJS) is a rare autosomal dominant disorder characterized by hamartomatous polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. Patients are at high risk for complications such as bleeding, obstruction, and especially small-bowel intussusception, which often occurs in childhood or adolescence. Early recognition is essential, as intussusception can be the first life-threatening presentation of PJS. This case highlights the importance of considering PJS in young patients presenting with acute intestinal obstruction. A 16-year-old male with no medical history presented with 48 hours of diffuse abdominal pain, vomiting, cessation of feces and flatus, and melena. Examination showed generalized abdominal guarding and a palpable left-flank mass. Laboratory tests revealed leukocytosis, elevated CRP, metabolic acidosis, and high lactate. CT scan demonstrated a jejuno-jejunal intussusception with suspected distal ileal intussusceptions. Emergency laparotomy revealed a 2-meter gangrenous jejuno-jejunal intussusception and two additional ileal invaginations caused by polypoid lesions. A segmental small-bowel resection with primary anastomosis and enterotomy for polyp removal was performed. Histology confirmed multiple hamartomatous polyps consistent with PJS. The postoperative course was favorable, and the patient was referred for genetic counseling and surveillance. PJS often presents with gastrointestinal polyps that can act as lead points for intussusception. Up to 69% of patients experience at least one episode, particularly in adolescence. Multiple synchronous intussusceptions, as in this case, require thorough intraoperative evaluation of the entire small bowel to identify additional polyps and prevent recurrence. While bowel preservation through reduction and polypectomy is preferred, extensive resection may be necessary when ischemia or necrosis is present. Long-term management includes routine endoscopic surveillance, removal of polyps ≥15 mm, and monitoring for the significantly elevated lifetime risk of gastrointestinal and extra-intestinal malignancies. Genetic counseling is critical for confirming STK11 mutations and informing family screening. This case demonstrates that PJS may initially present as severe, multifocal small-bowel intussusception in adolescents. Prompt diagnosis, surgical management, and comprehensive evaluation for additional polyps are essential to prevent recurrence and complications. Long-term multidisciplinary follow-up is vital due to the high risk of malignancy and recurrence inherent to PJS.
2026-03-28 | Genetic Predisposition to Pancreatic Cancer: A Systematic Review of Hereditary Syndromes and Familial Aggregation.
Pancreatic cancer is a highly lethal malignancy, with a 5-year survival rate of approximately 8%. Roughly 10% of cases occur in individuals with familial pancreatic cancer or identified high-risk germline mutations, including STK11, CDKN2A, BRCA1/2, MLH1, and MSH2. We aimed to evaluate the risk of pancreatic cancer associated with inherited genetic mutations and to characterize these genetic syndromes. A systematic search of the PubMed database up to 2024 identified 1500 articles, of which 90 met the criteria for inclusion in this review. High-risk individuals were defined as those with at least a 10-fold increased risk, moderate risk as 5-10-fold and low risk as under 5-fold. High-risk individuals included those with Peutz-Jeghers syndrome (132-140-fold risk), hereditary pancreatitis (50-87-fold risk), Familial Atypical Multiple Mole Melanoma syndrome (up to 48-fold risk), hereditary breast and ovarian cancer with BRCA2 mutation (up to 22-fold risk), and familial pancreatic cancer with at least three affected relatives (up to 32-fold risk). Moderate-risk patients had BRCA1, MLH1, MSH2, MSH6, p53, and ATM mutations, as well as familial pancreatic cancer with 1-2 affected kindred. Low-risk patients had familial adenomatous polyposis. Identifying high-risk individuals is crucial for effective genetic counseling, testing, and potential screening programs to facilitate early diagnosis and improve outcomes. Future research should prioritize large prospective cohorts, screening programs, and the integration of emerging technologies, such as AI-assisted imaging.
antibodies
2026-08-19 | Fibroblast heterogeneity in Peutz-Jeghers syndrome: identifying the polyp-driving subset†.
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder caused by germline mutations in STK11, and is characterized by gastrointestinal hamartomatous polyps, the recurrent development of which significantly impacts patients' quality of life. While stromal cells have been implicated in PJS polyp formation, their specific characteristics remain unclear. Domènech-Moreno et al identify polyp-enriched crypt top fibroblasts (pCTFs) as the pathogenic fibroblast population and demonstrate that interleukin (IL)-11, a major secretory factor produced by these cells, serves as a critical mediator linking STK11 deficiency to epithelial proliferation. The study reveals that Stk11 loss triggers IL-11 expression, which in turn reinforces the pathogenic pCTF phenotype through autocrine signaling, forming a feedforward loop. Importantly, IL-11 neutralization significantly reduces polyp formation in a faithful mouse model, providing strong preclinical evidence for therapeutic translation. This work represents a significant advance in our understanding of PJS pathogenesis and establishes IL-11 as a promising therapeutic target. Future investigations into the effects of IL-11 neutralization on established polyps will further refine the translational potential of these findings for preventive intervention strategies. © 2026 The Pathological Society of Great Britain and Ireland.
2026-01-23 | A novel effect of bevacizumab in reducing characteristic pigmentation in Peutz-Jeghers syndrome: a case report and literature review.
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by mucocutaneous pigmentation (e.g., perioral melanotic macules) and gastrointestinal hamartomatous polyps, with heightened cancer susceptibility. This report describes a 34-year-old Han Chinese ethnicity woman with familial Peutz-Jeghers syndrome (PJS) and stage IIA HPV-independent gastric-type endocervical adenocarcinoma following bevacizumab therapy. Initial concurrent chemoradiation (paclitaxel with either nedaplatin or cisplatin with volumetric modulated arc therapy) achieved partial response, while subsequent maintenance therapy combining bevacizumab with chemotherapy induced complete radiographic remission. Crucially, progressive fading of pathognomonic perioral melanotic macules demonstrated temporal correlation with bevacizumab administration, with sustained remission at 1-year follow-up. These findings challenge the conventional paradigm of PJS pigmentation as a static feature by demonstrating that VEGF-mediated angiogenesis concurrently drives carcinogenesis and melanin deposition. The case highlights three key implications, namely: (1) validation of bevacizumab's dual therapeutic potential against PJS-associated malignancies and cutaneous manifestations, (2) proposal of mucocutaneous pigmentation as a dynamic biomarker for treatment response monitoring, and (3) urgent need for prospective clinical trials evaluating VEGF inhibition in PJS through longitudinal surveillance of oncologic control and pigment dynamics.
2025-06-20 | IL-17 links the tumor suppressor LKB1 to gastrointestinal inflammation and polyposis.
Mutations in the tumor suppressor liver kinase B1 (LKB1) promote the development of gastrointestinal (GI) polyps of unknown etiology. Here, we identify IL-17 as a novel driver of LKB1-dependent polyp growth. GI tumors from mice bearing heterozygous mutations in Stk11 (which encodes LKB1) display signatures of pathogenic IL-17-producing CD4+ T helper 17 (TH17) cells. LKB1 constrains T cell inflammatory potential, as Stk11/LKB1 haploinsufficiency promotes T cell differentiation toward pathogenic IL-17-producing T cell lineages (CD4+ TH17 and CD8+ Tc17) in vitro and following intestinal infection. Mechanistically, aberrant CREB-regulated transcription coactivator 2 (CRTC2)-dependent signaling drives pathogenic TH17 cell programs downstream of LKB1 haploinsufficiency. Targeting this circuit via CRTC2 deletion or IL-17 blockade antagonizes GI polyp growth in mouse models of Peutz-Jeghers syndrome. These findings establish LKB1 as a gatekeeper of inflammatory type 3 (IL-17-dependent) T cell responses and identify a CRTC2-IL-17 signaling axis that can be targeted therapeutically to block the growth of LKB1 mutant GI tumors.
2025-03-12 | Interleukin-11 expressed in the polyp-enriched fibroblast subset is a potential therapeutic target in Peutz-Jeghers syndrome.
Peutz-Jeghers syndrome (PJS) is associated with early-onset gastrointestinal polyposis caused by hereditary inactivating pathogenic variants in the tumor suppressor gene STK11 (LKB1). Due to lack of prophylactic therapies, management of PJS polyps requires frequent surveillance. Interestingly, studies in mouse models have revealed that stromal cells drive the polyp formation, but detailed understanding of the cell types and interactions involved has been lacking. Using single-cell RNA sequencing of PJS mouse model polyps, we here identify a polyp-enriched crypt top fibroblast (pCTF) cluster characterized by a transcriptional signature also enriched in PJS patient polyps. The pCTF signature was also noted in primary fibroblasts in vitro following acute STK11 loss. Targeted deletion of Stk11 in crypt top fibroblasts using Foxl1-Cre led to upregulation of the pCTF signature genes and later to polyposis. pCTFs displayed similarity to inflammation-associated fibroblasts, and polyposis was exacerbated by inflammation. Cell-cell communication analysis identified interleukin 11 (IL-11) as a potential pCTF inducer, and consistent with this, IL-11 was required for fibroblast reprogramming toward pCTFs following STK11 loss. Importantly, a neutralizing IL-11 antibody efficiently reduced polyp formation in a PJS model indicating a key, targetable role for IL-11 in polyp development. Together the results characterize pCTFs as a PJS polyp-enriched fibroblast subset and identify IL-11 as a key mediator of fibroblast reprogramming and a potential therapeutic target in PJS. © 2025 The Pathological Society of Great Britain and Ireland.
2025-02-28 | Gastric-type endocervical adenocarcinoma, superficial myofibroblastoma, sex cord-stromal tumors, and HSIL in Peutz-Jeghers syndrome: a rare case report, genetic characterization, and review of literature.
Peutz-Jeghers syndrome (PJS) is characterized by an increased risk of gynecologic tumors. Gastric-type endocervical adenocarcinoma (GEA) is a rare non-human papillomavirus (HPV)-related tumor. We reported an uncommon case of a 39-year-old woman with PJS who developed GEA, superficial cervical vaginal myofibroblastoma, sex cord-stromal tumors with annular tubules of the ovaries, and cervical and vaginal high-grade squamous interepithelial neoplasia (HSIL). Before being verified GEA, the patient had been experiencing suspicious symptoms for over 9 years, with nabothian cysts and vaginitis being misdiagnosed. HSIL displayed widespread p16 immunostaining, and HPV DNA screening confirmed HPV-18 infection, although GEA was negative. Further, we verified TP53 mutation and HER2 amplification of GEA by fluorescence in situ hybridization (FISH). TP53 was the most commonly mutated gene. The therapy with the anti-HER2 antibody trastuzumab was suggested based on HER2 amplification. We also analyzed the somatic mutations of GEA by whole genome sequencing (WES). There were 157 single nucleotide variations (SNVs) and 215 indels, with all of them being heterozygotes. Nonsynonymous and frameshift insertions were the most common kinds of mutations. The germine STK11 gene mutation was found, which may play an important role in tumor development. According to gene function enrichment analyses, the genomic changes primarily implicated general transcription or expression pathways and cell cycle pathways. In addition, the JAK2/STAT3 pathway could be a major focus of targeted therapy for GEA patients with PJS. Our findings show that the patient with PJS can have a variety of unusual gynecologic tumors. Patients with PJS must have routine gynecological, ultrasonographic, and cytological examinations to detect precursor or early-stage lesions. The patient's abnormal symptoms must be treated early with caution. A comprehensive genomic study reveals the potential causative genetic factors, therapeutic targets, and chemotherapy resistance of GEA. Further research will focus on the main driving genes, molecular mechanisms, and molecular target therapy in more patients.
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2026-02-23 | Ischemic polypectomy for small-bowel polyps in pediatric Peutz-Jeghers syndrome.
Peutz-Jeghers syndrome (PJS) is characterized by the development of hamartomatous polyps in the gastrointestinal tract that can cause chronic blood loss. Ischemic polypectomy has emerged as a low-risk technique in adult patients with PJS but remains largely undocumented in pediatric populations. This video presents the first published case demonstrating ischemic polypectomy in a pediatric patient, to our knowledge. A 12-year-old girl with PJS and chronic anemia underwent balloon-assisted enteroscopy. Seven pedunculated small-bowel polyps were identified and treated using ischemic polypectomy with a detachable snare. Three representative polypectomies are shown. The snare was tightened at the polyp stalk until ischemic changes occurred, then cinched and deployed. One instance required a second snare because of equipment malfunction. All polyps were successfully treated without electrocautery, bleeding, or perforation. Follow-up demonstrated improvement in longstanding anemia, with a rise in hemoglobin from 9.1 to 12.4 g/dL at 6 weeks, supporting therapeutic benefit. Repeat capsule endoscopy was planned. Ischemic polypectomy using balloon-assisted enteroscopy is feasible, effective, and safe in pediatric PJS. By avoiding thermal energy, it may reduce the risk of transmural injury and represents a valuable option for children with numerous pedunculated small-bowel polyps.
2022-02-21 | RETRACTED ARTICLE: Multidisciplinary management for Peutz–Jeghers syndrome and prevention of vertical transmission to offspring using preimplantation genetic testing
Peutz Jeghers syndrome (PJS) is an autosomal dominant genetic disorder caused by STK11 mutation with a predisposition to gastrointestinal polyposis and cancer. PJS patients suffer poor quality of life and are highly concerned about whether deleterious mutations transmit to their offspring. Therefore, this study aimed to propose feasible clinical management and provide effective preimplantation genetic testing for monogenic defect (PGT-M) strategies to protect offspring from inheriting the disease.A hospital-based clinical retrospective analysis reviewing the clinical characteristics and fertility aspects was first conducted on 51 PJS patients at the First Affiliated Hospital of Zhengzhou University between January 2016 and March 2021. Among the 51 patients, the PGT-M strategy was further carried out in 4 couples, which started with a biopsy of the trophectoderm cells of embryos and whole genome amplification using multiple displacement amplification. Thereafter, single nucleotide polymorphism linkage analyses based on karyomapping were performed with copy number variations of the embryos identified simultaneously. Finally, prenatal diagnosis was used to verify the validity of the PGT-M results.A comprehensive management flowchart adopted by the multidisciplinary team model was formulated mainly focusing on clinical genetic and gastrointestinal aspects. Under the guidelines of this management, 32 embryos from 4 PJS pedigrees were diagnosed and 2 couples successfully conceived healthy babies free of the STK11 pathogenic mutation.Our comprehensive management could help affected families avoid having children with PJS through preimplantation genetic testing and provide meaningful guidance for multidisciplinary clinical practice on PJS.
2013-09-02 | LKB1 mutant in a KRAS activated adenocarcinoma of the lung associated with Peutz–Jeghers syndrome: A case report
We present a case of a 54-year-old woman who was diagnosed with a KRAS positive adenocarcinoma of the lung on the basis of a Peutz-Jeghers syndrome (PJS), which was unknown before. PJS is a rare hereditary disease, which may be associated with the development of poor outcome adenocarcinomas and LKB1-gene mutations. A very rare type of a LKB1 mutation was found, not previously described in lung cancer. Although seldom screened for LKB-1 mutations are found in up to 30% of lung adenocarcinomas and may be druggable therapeutic targets, in particular in KRAS mutant tumours in the near future as recent preclinical results with nucleotides demonstrate.
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