Peutz-Jeghers Syndrome


Peutz-Jeghers syndrome (PJS) is an autosomal-dominant condition characterized by the gastrointestinal polyposis, mucocutaneous pigmentation, and predisposition to a range of epithelial cancers: including colorectal, gastric, pancreatic, breast, and ovarian cancers. Women also have increased risk of sex cord tumors with annular tubules. Approximately 45% of affected individuals have no family history of PJS. (GeneReviews)

Literature Analysis

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Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (2)

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STK11 19p13.3 PJS, LKB1, hLKB1 Germline
-STK11 mutations in Peutz-Jeghers Syndrome
PRSS1 7q34 TRP1, TRY1, TRY4, TRYP1 -PRSS1 and Peutz-Jeghers Syndrome

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Useful links (6 links)

Latest Publications

Jelsig AM
Hamartomatous polyps - a clinical and molecular genetic study.
Dan Med J. 2016; 63(8) [PubMed] Related Publications
Hamartomatous polyps (HPs) in the gastrointestinal (GI) tract are rare compared to other types of GI polyps, yet they are the most common type of polyp in children. The symptoms are usually rectal bleeding, abdominal pain, obstipation, anaemia, and/or small bowel obstruction. The polyps are typically removed concurrently with endoscopy when located in the colon, rectum, or stomach, whereas polyps in the small bowel are removed during push-enteroscopy, device-assisted enteroscopy, or by surgery. HPs can be classified as juvenile polyps or Peutz-Jeghers polyps based on their histopathological appearance. Patients with one or a few juvenile polyps are usually not offered clinical follow-up as the polyp(s) are considered not to harbour any malignant potential. Nevertheless, it is important to note that juvenile polyps and HPs are also found in patients with hereditary hamartomatous polyposis syndromes (HPS). Patients with HPS have an increased risk of cancer, recurrences of polyps, and extraintestinal complications. The syndromes are important to diagnose, as patients should be offered surveillance from childhood or early adolescence. The syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and the PTEN hamartoma tumour syndrome. Currently, the HPS diagnoses are based on clinical criteria and are often assisted with genetic testing as candidate genes have been described for each syndrome. This thesis is based on six scientific papers. The overall aim of the studies was to expand the knowledge on clinical course and molecular genetics in patients with HPs and HPS, and to investigate research participants' attitude towards the results of extensive genetic testing.   Paper I: In the first paper we investigated the occurrence, anatomic distribution, and other demographics of juvenile polyps in the colon and rectum in Denmark in 1995-2014. Based on the Danish Pathology Data Bank we found that 1772 patients had 2108 JPs examined in the period, and we calculated the incidence of juvenile polyps to be between 1:45,000 and 1:65,000. The majority of patients with juvenile polyps were adults and 1% fulfilled to diagnostic criteria of JPS. The majority of patients had a single juvenile polyp. Paper II: In this paper we conducted a review of the HPS based on the current literature. Paper III: We investigated the hypothesis that patients with one or few HPs may have a HPS based on genetic screening. We de-signed a panel of 26 genes associated with HPS and used targeted next generation sequencing in 77 patients with mainly one juvenile polyp. We detected several germ line variants, among them three in ENG, two in BMPR1A, one in PTEN, and one in SMAD4. Although some of the detected variants have been reported previously none could be classified as definitely pathogenic or likely pathogenic according to our variant classification scheme and thus we concluded that genetic screening of patients with one or few JPs are not indicated. Paper IV: In Paper IV we investigated one of the ethical aspects of next generation sequencing: the issue whether research participants in NGS studies should be offered the possibility of not re-ceiving information on incidental genetic findings (the "opting out possibility"). We conducted semi-structures interviews in 127 research participants, and found that the majority (61%) wanted information on all incidentals findings, while 36% wanted information on actionable incidental findings. Only 3% did not want information on incidental findings at all. Paper V: In this paper we wanted to gather information on all Danish patients with Peutz-Jeghers syndrome in order to investigate the phenotype and genotype. Through Danish registers we detected 43 patients of which 14 had deceased. We calculated the prevalence of Peutz-Jeghers syndrome to be approximately one in 195,000 individuals. The median age at diagnosis was 29 years with obstruction of the small bowel as the most frequent presenting symptom. We noted 18 cancer occurrences in the population in both the GI tract and at extraintestinal sites, demonstrating that these patients are predisposed to cancer at various anatomical sites. The study also underlined the wide phenotypic expression of the syndrome.   Paper VI: In the last paper we identified patients with juvenile polyposis syndrome, who carry a SMAD4 mutation, and described their genotype and phenotype. We especially investigated whether these patients have symptoms of both juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia. We identified 14 Danish patients. Most of these had symptoms of both conditions and one had aortic root dilatation. Thus, this group of patients requires a multidisciplinary follow-up program.

Kazubskaya TP, Kozlova VM, Filippova MG, et al.
[Rare hereditary syndromes associated with polyposis and the development of malignant tumors].
Arkh Patol. 2016 Mar-Apr; 78(2):10-8 [PubMed] Related Publications
UNLABELLED: Familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome are genetic diseases characterized by gastrointestinal polyps, extraintestinal manifestations, and autosomal dominant inheritance. The carriers of these diseases from early childhood are at risk for neoplasias at different sites, which are symptomatic at various ages.
AIM: to study the clinical organ-specific manifestations in patients with FAP and Peutz-Jeghers, genetics update and possibilities of diagnosis, monitoring, and treatment of these diseases.
MATERIAL AND METHODS: The authors give the results of their examination and follow-up of children with FAP and Peutz-Jeghers hamartoma-polypous syndrome. In addition, current data from PubMed, Medline (including reviews, original articles and case reports) were used.
RESULTS: The main clinical organ-specific signs of multiple tumors in FAP and Peutz-Jeghers syndrome are shown. Data on the assessment of a risk for malignant tumors at various sites in the affected patients and their family members at different ages are provided. Each of these syndromes has a dissimilar genetic foundation. FAP is caused by the germline mutations in the APC gene, Peutz-Jeghers syndrome is by the STK11 gene, which predispose individuals to specifically associated neoplasias and require different follow-up strategies. Information on a phenotype-genotype correlation may serve as a reference point for the possible severity and various manifestations of a disease. An update on the molecular pathogenesis of these diseases is considered.
CONCLUSION: Molecular genetic testing of the genes associated with FAP and Peutz-Jeghers syndromes makes it possible to timely recognize family members at high risk, to plan therapeutic strategy and to affect the course of a disease. The joint participation of pediatricians, proctologists, oncologists, morphologists, geneticists, and molecular biologists is essential to timely recognize the carriers of the syndromes and a better prognosis in these patients.

Mao X, Zhang Y, Wang H, et al.
[Mutations of the STK11 and FHIT genes among patients with Peutz-Jeghers syndrome].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2016; 33(2):186-90 [PubMed] Related Publications
OBJECTIVE: To correlate the clinical characteristics with mutations of the STK11 and FHIT genes in 16 patients with Peutz-Jeghers syndrome (PJS).
METHODS: Potential mutations in the coding regions and flanking sequences of the STK11 and FHIT genes were detected with PCR and Sanger sequencing.
RESULTS: Of the 16 patients with PJS, 8 had novel mutations in the coding region of the STK11 gene, 1 had a previously reported mutation. 1 carried a mutation in the exon 10 of the FHIT gene, which is a non-coding region. None of the mutations was detected in the immediate family members. None of the patients with STK11 gene mutations had mutation in the FHIT gene. The mutation rate of the STK11 gene among patients with PJS was 56.25%.
CONCLUSION: Mutations of the STK11 gene are the major cause of PJS. Few such patients had mutations of the FHIT gene. Mutations of the FHIT gene may play a part in the pathogenesis of PJS.

Huang ZH, Song Z, Zhang P, et al.
Clinical features, endoscopic polypectomy and STK11 gene mutation in a nine-month-old Peutz-Jeghers syndrome Chinese infant.
World J Gastroenterol. 2016; 22(11):3261-7 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate multiple polyps in a Chinese Peutz-Jeghers syndrome (PJS) infant.
METHODS: A nine-month-old PJS infant was admitted to our hospital for recurrent prolapsed rectal polyps for one month. The clinical characteristics, a colonoscopic image, the pathological characteristics of the polyps and X-ray images of the intestinal perforation were obtained. Serine threonine-protein kinase 11 (STK11) gene analysis was also performed using a DNA sample from this infant.
RESULTS: Here we describe the youngest known Chinese infant with PJS. Five polyps, including a giant polyp of approximately 4 cm × 2 cm in size, were removed from the infant's intestine. Laparotomy was performed to repair a perforation caused by pneumoperitoneum. The pathological results showed that this child had PJS. Molecular analysis of the STK11 gene further revealed a novel frameshift mutation (c.64_65het_delAT) in exon 1 in this PJS infant.
CONCLUSION: The appropriate treatment method for multiple polyps in an infant must be carefully considered. Our results also show that the STK11 gene mutation is the primary cause of PJS.

Huang Z, Miao S, Wang L, et al.
Clinical characteristics and STK11 gene mutations in Chinese children with Peutz-Jeghers syndrome.
BMC Gastroenterol. 2015; 15:166 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disease characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin spots. Germline mutation of the serine/threonine kinase 11 (STK11) gene are responsible for PJS. In this study, we investigated the clinical characteristics and molecular basis of the disease in Chinese children with PJS.
METHODS: Thirteen children diagnosed with PJS in our hospital were enrolled in this study from 2011 to 2015, and their clinical data on polyp characteristics, intussusceptions events, family histories, etc. were described. Genomic DNA was extracted from whole-blood samples from each subject, and the entire coding sequence of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing.
RESULTS: The median age at the onset of symptoms was 2 years and 4 months. To date, these children have undergone 40 endoscopy screenings, 17 laparotomies and 9 intussusceptions. Polyps were found in the stomach, duodenum, small bowel, colon and rectum, with large polyps found in 7 children. Mutations were found in eleven children, including seven novel mutations (c.481het_dupA, c.943_944het_delCCinsG, c.397het_delG, c.862 + 1G > G/A, c.348_349het_delGT, and c.803_804het_delGGinsC and c.121_139de l19insTT) and four previously reported mutations (c.658C > C/T, c.890G > G/A, c.1062 C > C/G, and c.290 + 1G > G/A). One PJS patient did not have any STK11 mutations.
CONCLUSIONS: The polyps caused significant clinical consequences in children with PJS, and mutations of the STK11 gene are generally the cause of PJS in Chinese children. This study expands the spectrum of known STK11 gene mutations.

Brito S, Póvoas M, Dupont J, Lopes AI
Peutz-Jeghers syndrome: early clinical expression of a new STK11 gene variant.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
Genetic heterogeneity has been recognised in Peutz-Jeghers syndrome (PJS) (over 230 STK11 gene mutations reported). We report a rare PJS phenotype with early extensive gastrointestinal (GI) presentation and a new genetic variant. The case presented as haematochezia and mucocutaneous pigmentation (the patient was 3 years of age). Endoscopy showed several polyps throughout the stomach/colon (PJ-type hamartomas); the larger polyps were resected. Small bowel imaging detected multiple jejunum/ileum small polyps. During 8 years of follow-up of this asymptomatic patient, an increasing number of diffusely distributed polyps was observed and polypectomies were performed. Subsequently, the patient failed consultations; when the patient was 13 years of age, emergency surgery was required due to small bowel intussusception (ileal polyp). A STK11 gene study identified two missense variants in heterozygous (yet unknown significance but probably pathogenic): c.854T>A (exon 6) and c.446C>T* (exon 2) (*not previously reported). We report two STK11 gene variants (one not previously described) of yet undetermined causality in a paediatric patient presenting with extensive GI involvement at a very early age, with no family medical history. Structural and functional repercussion of the newly described variants should be further investigated.

Li N, Huang D, Lu N, Luo L
Role of the LKB1/AMPK pathway in tumor invasion and metastasis of cancer cells (Review).
Oncol Rep. 2015; 34(6):2821-6 [PubMed] Related Publications
Liver kinase B1 (LKB1), also known as serine/threo-nine kinase 11 (STK11), is a tumor suppressor that is inactivated in Peutz-Jeghers familial cancer syndrome. LKB1 phosphorylates and activates AMP-activated protein kinase (AMPK), which negatively regulates cancer cell proliferation and metabolism. However, recent evidence demonstrates that the LKB1/AMPK pathway is involved in the process of tumor invasion and migration, which is an important hallmark of carcinoma progression to higher pathological grades of malignancy. This review focuses on the function of the LKB1/AMPK pathway in the invasion and migration of cancer cells and provides an overview of therapeutic strategies aimed at this pathway in malignant tumors.

McKay V, Cairns D, Gokhale D, et al.
First report of somatic mosaicism for mutations in STK11 in four patients with Peutz-Jeghers syndrome.
Fam Cancer. 2016; 15(1):57-61 [PubMed] Related Publications
Peutz-Jeghers syndrome (PJS) is an autosomal dominant cancer predisposition syndrome characterised by gastrointestinal polyposis and mucocutaneous pigmentation. Mutations in STK11, a serine-threonine protein kinase, have been associated with PJS in up to 100 % of published series. The hypothesis that a further genetic locus for PJS exists is controversial. No mutations in any other genes have been described in association with PJS. To date, no instances of somatic mosaicism for STK11 have been described. DNA extracted from peripheral lymphocytes and buccal cells was screened by sequence analysis for mutations in STK11. Dosage analysis was undertaken by multiplex ligation-dependent probe amplification (MLPA). Four patients have been shown to have mosaicism in STK11: two had mosaic deletions of specific exons (2-3 and 3-10) of the STK11 gene; one had a mosaic nonsense mutation in exon 5; and one had a mosaic frameshift mutation in exon 8. This report details the first four reported cases of somatic mosaicism for STK11 associated with PJS. This shows that techniques in addition to direct sequencing such as MLPA must be used to assess for large scale genomic deletions in patients meeting clinical diagnostic criteria for PJS. This also adds further weight to the hypothesis of a single genetic locus for PJS.

Fu J, Wen Z, Wang F, et al.
Genetic and Clinical Analyses of Southern Chinese Children with Peutz-Jeghers Syndrome.
Genet Test Mol Biomarkers. 2015; 19(9):528-31 [PubMed] Related Publications
BACKGROUND: Children with Peutz-Jeghers syndrome (PJS) suffer from the continuous growth of polyps in their gastrointestinal tracts. Limited research on PJS has found that truncating mutations of the serine/threonine kinase 11 (STK11) gene may correlate with early symptoms and a greater number of polyps. Thus, further studies correlating the genetic and clinical characteristics of PJS would increase our understanding of this condition and improve recommendations for treatment.
AIMS: Our study was designed to characterize the genetic and clinical characteristics of four Chinese PJS children (two girls and two boys) and their affected relatives from Southern China.
RESULTS: One recurrent missense mutation (c.487G>C) and two novel nonsense (truncation) mutations (c.717G>A and c.871G>T) in the STK11 gene were identified. The two boys with nonsense mutations underwent their first surgeries at younger ages (2 and 4 years) compared to the others. The two girls underwent their first surgeries at similar ages, though the girl with the nonsense mutation underwent more surgeries than the girl with the missense mutation. The children with truncation mutations had medium to high counts of hamartomatous polyps, whereas the girl with the missense mutation had a lower count. The clinical findings were similar among affected individuals within each of the three families.
CONCLUSIONS: These cases are consistent with previous findings, thus we conclude that children with nonsense mutations in STK11 should be closely monitored for polyp formation.

Peng WX, Kure S, Ishino K, et al.
P16-positive continuous minimal deviation adenocarcinoma and gastric type adenocarcinoma in a patient with Peutz-Jeghers syndrome.
Int J Clin Exp Pathol. 2015; 8(5):5877-82 [PubMed] Free Access to Full Article Related Publications
We report a case of Peutz-Jeghers syndrome (PJS) in a 33-year-old female patient with synchronous uterine cervical minimal deviation adenocarcinoma (MDA) and gastric type adenocarcinoma (GTA). The patient was diagnosed with PJS at the age of 10. At the time of consultation, she complained of watery discharge. Magnetic resonance imaging of the pelvis showed a poorly circumscribed mass in the uterine cervix. Histologically, both MDA and GTA components, as well as their transitional area, were observed. Both components were diffusely positive for MUC6, CK7 and, robustly, for p16. Moreover, the components were negative for ER, PgR and CEA, while HIK1083 and CK20 positive cells were found focally. Ki-67 labeling index in the MDA component was 5% while that in the GTA component was 50%. This case of GTA accompanied by MDA in a patient with PJS is distinct from the single previously-reported comparable case of which we are aware, with respect to the overexpression of p16 protein, an event considered rare in these tumors, and the continuity between the MDA and GTA components. This continuity favors the hypothesis that GTA arises from the dedifferentiation of MDA.

Smith KJ, Germain M
Polycystic ovary syndrome (PCOS) with melanocytic mucosal macules: the role of STK11 gene polymorphisms in PCOS and Peutz-Jeghers syndrome.
Int J Dermatol. 2016; 55(2):177-80 [PubMed] Related Publications
BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex genetic disorder that is the most common endocrinopathy that affects women.
OBSERVATIONS: We report two individuals with PCOS with a genetic polymorphism in serine threonine kinase 11 (STK11). Both these individuals developed mucosal pigmentation suggesting Peutz-Jeghers syndrome (PJS), which is associated with mutations in STK11. Both individuals showed some improvement in their metabolic and endocrine dysregulation with therapies commonly used for PCOS. However, they continued to show progression of mucosa pigmentation.
CONCLUSIONS: This is the first report of clinical overlap in individuals with PCOS and PJS, even though some individuals with PCOS show a polymorphism in STK11, which is the gene mutated in PJS. The importance of this clinical association is not clear but may be significant because of the association of STK11 dysregulation and the development of internal tumors.

Ngeow J, Yu W, Yehia L, et al.
Exome Sequencing Reveals Germline SMAD9 Mutation That Reduces Phosphatase and Tensin Homolog Expression and Is Associated With Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas.
Gastroenterology. 2015; 149(4):886-9.e5 [PubMed] Related Publications
Hamartomatous polyposis syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial juvenile polyposis syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 (SMAD9(V90M)). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9(V90M) had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments.

Borun P, De Rosa M, Nedoszytko B, et al.
Specific Alu elements involved in a significant percentage of copy number variations of the STK11 gene in patients with Peutz-Jeghers syndrome.
Fam Cancer. 2015; 14(3):455-61 [PubMed] Free Access to Full Article Related Publications
Peutz-Jeghers syndrome (PJS) is a rare hereditary syndrome characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation and increased risk of cancer in multiple internal organs. PJS is preconditioned by the manifestation of mutations in the STK11 gene. The majority of detected STK11 changes are small scale mutations, however recent studies showed the significant contribution of medium-sized changes commonly known as copy number variations (CNVs). Here we present a novel 7001 bps deletion of STK11 gene fragment, in which we identified the presence of breakpoints (BPs) within the Alu elements. Comparative meta-analysis with the 80 other CNV cases from 12 publications describing STK11 mutations in patients with PJS revealed the participation of specific Alu elements in all deletions of exons 2-3 so far described. Moreover, we have shown their involvement in the two other CNVs, deletion of exon 2 and deletion of exon 1-3 respectively. Deletion of exons 2-3 of the STK11 gene may prove to be the most recurrent large rearrangement causing PJS. In addition, the sequences present in its BPs may be involved in a formation of a significant percentage of the remaining gene CNVs. This gives a new insight into the conditioning of this rare disease and enables improvements in PJS genetic diagnostics.

Syngal S, Brand RE, Church JM, et al.
ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
Am J Gastroenterol. 2015; 110(2):223-62; quiz 263 [PubMed] Free Access to Full Article Related Publications
This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

Kuroda Y, Saito T, Nagai J, et al.
Microdeletion of 19p13.3 in a girl with Peutz-Jeghers syndrome, intellectual disability, hypotonia, and distinctive features.
Am J Med Genet A. 2015; 167A(2):389-93 [PubMed] Related Publications
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disease characterized by gastrointestinal polyposis and mucocutaneous pigmentation. Germline point mutations in the serine/threonine kinase 11 (STK11) have been identified in about 70% of patients with PJS. Only a few large genomic deletions have been identified. We report on a girl with PJS and multiple congenital anomalies. She had intellectual disability, umbilical hernia, bilateral inguinal hernias, scoliosis, and distinct facial appearance including prominent mandible, smooth philtrum, and malformed ears. She developed lip pigmentation at the age of 12 years but had no gastrointestinal polyps. Array comparative genomic hybridization revealed an approximately 610 kb deletion at 19p13.3, encompassing STK11. Together with previous reports, the identification of common clinical features suggests that microdeletion at 19p13.3 encompassing STK11 constitutes a distinctive phenotype.

Forte G, Grossi V, Celestini V, et al.
Characterization of the rs2802292 SNP identifies FOXO3A as a modifier locus predicting cancer risk in patients with PJS and PHTS hamartomatous polyposis syndromes.
BMC Cancer. 2014; 14:661 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hamartomatous polyposis syndromes (HPS) are inherited conditions associated with high cancer risk. They include the Peutz-Jeghers and the PTEN hamartoma tumor syndromes, which are caused by mutations in the LKB1 and PTEN genes, respectively. Estimation of cancer risk is crucial in order to optimize surveillance, but no prognostic markers are currently available for these conditions. Our study relies on a 'signal transduction' hypothesis based on the crosstalk between LKB1/AMPK and PI3K/PTEN/Akt signaling at the level of the tumor suppressor protein FoxO3A. Interestingly, the FOXO3A rs2802292 G-allele was shown to be associated with longevity, reduced risk of aging-related diseases and increased expression of FoxO3A mRNA.
METHODS: We typed rs2802292 in 150 HPS unrelated patients and characterized the expression of FoxO3A by quantitative PCR and immunoblot analysis in human intestinal cell lines.
RESULTS: We found a significantly higher risk for malignancies in females and TT genotype carriers compared to patients having at least one G-allele. Subgroup analysis for each HPS syndrome revealed a G-allele-associated beneficial effect on cancer risk occurring mainly in males. Molecular characterization of human intestinal cell lines showed that the G-allele significantly correlated with increased basal expression of FoxO3A mRNA and protein.
CONCLUSION: Our results suggest an inverse correlation between the protective allele (G) copy number and cancer risk, and might be useful to optimize surveillance in HPS patients. Further investigations are needed to confirm our hypothesis and to ascertain whether differences in therapeutic response exist across genotypes.

Turpin A, Cattan S, Leclerc J, et al.
[Hereditary predisposition to cancers of the digestive tract, breast, gynecological and gonadal: focus on the Peutz-Jeghers].
Bull Cancer. 2014; 101(9):813-22 [PubMed] Related Publications
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disease due to mutations in the tumor suppressor gene STK11. PJS is characterized by periorificial hyperpigmented macules (lentiginosis) and hamartomatous polyposis. Polyps can be located anywhere in the gastrointestinal tract, but are preferably observed in the small bowel (70-90%), the colon (50%) and the stomach (25%). They tend to be cancerous in a particular sequence hamartoma-dysplasia-cancer. The diagnosis is often made in the first or second decade following the appearance of lentigines or upon the occurrence of complications due to polyps (obstruction, intussusception, occult bleeding responsible for anemia). Furthermore PJS is associated with a significant increase in cancer risk (relative risk of 89% over the life according to the most recent series). Digestive cancers are the more frequent with cumulative incidences of 55% for gastro-intestinal cancer (39% for colorectal cancer, 13% for small bowel cancer and between 11 and 36% for pancreatic cancer, respectively). There is also an increased risk of non digestive cancers. In particular the risk of breast cancer is similar to that of patients carrying deleterious BRCA1 or BRCA2 mutations (cumulative incidence of 45%). Gynecological and gonadal tumors are frequent as well and can be more (adenoma malignum) or less aggressive (ovarian sex cord tumors with annular tubules and testicular tumors with calcified Sertoli cells). Finally the frequency of lung cancer is moderately increased. Recommendations for screening and management based on retrospective series in the literature have led to various strategies. The aim of this paper is to summarize the clinical and molecular diagnostic criteria of PJS as well as recommendations on screening strategies, management and monitoring.

Zhao X, Huang Y, Yang B, Zhao Y
[Mutation analysis of STK11 gene in a Chinese family with Peutz-Jeghers syndrome].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014; 31(3):294-7 [PubMed] Related Publications
OBJECTIVE: To investigate STK11 gene mutation in a pedigree with Peutz-Jeghers syndrome (PJS).
METHODS: A pedigree of PJS was investigated. DNA was extracted from peripheral blood samples from affected and unaffected members of the pedigree and 100 unrelated healthy controls. PCR was performed to amplify all of the 9 coding exons of STK11 gene. PCR products were directly sequenced to detect mutation.
RESULTS: A missense mutation p.F354L (c.1062C>G) in exon 8 of the STK11 gene has been identified in all patients with PJS, but was not found in normal individuals from the pedigree and 100 unrelated controls.
CONCLUSION: A missense mutation p.F354L of STK11 gene probably underlies the disease in this pedigree.

Wang Z, Wu B, Mosig RA, et al.
STK11 domain XI mutations: candidate genetic drivers leading to the development of dysplastic polyps in Peutz-Jeghers syndrome.
Hum Mutat. 2014; 35(7):851-8 [PubMed] Related Publications
Peutz-Jeghers syndrome (PJS) is a rare hereditary disorder resulting from mutations in serine/threonine kinase 11 (STK11) and characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous pigmentation, and an increased risk for specific cancers. Little is known about the genetic implications of specific STK11 mutations with regard to their role in dysplastic and malignant transformation of GI polyps. Peripheral blood genomic DNA samples from 116 Chinese PJS patients from 52 unrelated families were investigated for STK11 mutations. Genotype-phenotype correlations were investigated. The mutation detection rate was 67.3% (51.9% point mutations, 15.4% large deletions). Fourteen out of the 25 point mutations identified were novel. Nearly one-third of all mutations, 8/27 (29.6%), were in exon 7, the shortest out of the nine exons. Strikingly, mutations affecting protein kinase domain XI, encoded in part by exon 7, correlated with a 90% (9/10) incidence of GI polyp dysplasia. In contrast, only two out of 17 (11.8%) nondomain XI mutations were linked to polyp dysplasia (P = 0.0001). The extent of the association between dysplasia and the development of GI-related cancers is currently unknown but our results highlight a novel STK11 genotype-phenotype association as the basis for future genetic counseling and basic research studies.

Dai L, Fu L, Liu D, et al.
Novel and recurrent mutations of STK11 gene in six Chinese cases with Peutz-Jeghers syndrome.
Dig Dis Sci. 2014; 59(8):1856-61 [PubMed] Related Publications
BACKGROUND: The serine/threonine kinase 11 (STK11) gene is the main causal gene in Peutz-Jeghers syndrome (PJS). Abnormal STK11 may increase cancer risk of PJS patients via affecting its target proteins such as P53, AMPK, and PTEN. In this study, we investigated the molecular basis of six Chinese PJS patients.
MATERIALS AND METHODS: Blood samples were collected from four Chinese PJS families and two sporadic patients. The entire coding region of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing. Functions of mutants were assessed by PolyPhen-2, Swiss-Model software, and luciferase reporter assay.
RESULTS: Novel mutations (c.842_843insC, c.804_805insG, and c.922T>G) and recurrent mutations (c.526G>A, c.180C>G, and c.1062C>G) were identified. Missense mutation c.922T>G and c.526G>A were predicted as probably damaging by PolyPhen-2, while c.1062C>G was benign. Mutation c.108C>G was a nonsense mutation. The 284Ter mutants of c.842_843insC and c.804_805insG significantly diminished the capacity of P53 activity in 293FT cells.
CONCLUSIONS: Our results support that STK11 gene mutations underlie Chinese patients with PJS. Mutation involving partial kinase domain disrupts normal function of STK11. Our results also enlarge the spectrum of STK11 variants in PJS patients.

Kobayashi Y, Masuda K, Kimura T, et al.
A tumor of the uterine cervix with a complex histology in a Peutz-Jeghers syndrome patient with genomic deletion of the STK11 exon 1 region.
Future Oncol. 2014; 10(2):171-7 [PubMed] Related Publications
Patients with Peutz-Jeghers syndrome (PJS) have a risk of complicating malignant tumors, including cancer of the uterine cervix. Mutations in the STK11 gene have been identified as being responsible for PJS. However, the genotype-phenotype correlation in PJS is poorly understood, especially with respect to malignant tumors. Here, we report a detailed analysis of a case of a cervical tumor in a PJS patient showing a large genomic deletion in exon 1 of STK11 without human papillomavirus infection. Histological examination revealed a complex histology consisting of three components: lobular endocervical gland hyperplasia (LEGH), minimal deviation adenocarcinoma (MDA) and mucinous adenocarcinoma. Immunohistochemistry for STK11 was positive in the LEGH and MDA components, while that of the mucinous adenocarcinoma stained very faintly. These findings support a close relationship among LEGH, MDA and mucinous adenocarcinoma and imply that inactivation of STK11 may occur during progression from MDA to mucinous adenocarcinoma.

Wang HH, Xie NN, Li QY, et al.
Exome sequencing revealed novel germline mutations in Chinese Peutz-Jeghers syndrome patients.
Dig Dis Sci. 2014; 59(1):64-71 [PubMed] Related Publications
BACKGROUND AND AIMS: Peutz-Jeghers Syndrome (PJS) is an autosomal dominant disorder which predisposes to the development of various cancers. Germline mutation in the serine/threonine kinase 11 gene (STK11) is known as one of the major causes of PJS. However, a notable proportion of PJS samples do not carry any mutation in STK11, suggesting possible genetic heterogeneity in the disease and the existence of other causative variants.
METHODS AND RESULTS: In order to identify other germline variants in the coding regions of the genome that are associated with PJS, we performed exome sequencing in three Chinese individuals with PJS and identified 16 common germline variants (12 protein-coding including STK11, 4 in pre-microRNAs). We further validated protein-coding variants in six PJS individuals (three with wild-type STK11) and predicted the functional impact. As result, we found that 7 coding variants are likely to have functional impacts. Especially, we identified 2 new germline variants which are represented in all six PJS samples and are independent of STK11 mutation.
CONCLUSIONS: Our study provided an exomic view of PJS. The germline variants identified in our analysis may help to resolve the complex genetic background of the disease and thus lead to the discovery of novel causative variants of PJS.

Ham S, Meachem SJ, Choong CS, et al.
Overexpression of aromatase associated with loss of heterozygosity of the STK11 gene accounts for prepubertal gynecomastia in boys with Peutz-Jeghers syndrome.
J Clin Endocrinol Metab. 2013; 98(12):E1979-87 [PubMed] Related Publications
CONTEXT: Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder that arises as a consequence of mutations in the STK11 gene that encodes LKB1. PJS males often have estrogen excess manifesting as gynecomastia and advanced bone age. We and others have previously described an increase in testicular aromatase expression in PJS patients. However, the underlying mechanism has not yet been explored.
OBJECTIVE: The aim of this study was to characterize the role of LKB1 in regulating the expression of aromatase in boys with PJS via signaling pathways involving AMP-activated protein kinase (AMPK) and cyclic AMP-responsive element binding protein-regulated transcription coactivators (CRTCs).
PATIENTS: We studied testicular biopsies from two boys with STK11 mutations: a 13-year-old boy and an unrelated 4-year-old boy with prepubertal gynecomastia and advanced bone age, as well as breast tissue from the 13-year-old boy.
RESULTS: Loss of heterozygosity of STK11, measured by the absence of LKB1 immunofluorescence, was observed in Sertoli cells of abnormal cords of testis samples from affected individuals. This was associated with loss of p21 expression and decreased phosphorylation of AMPK, known downstream targets of LKB1, as well as the increased expression of aromatase. Similar results of low LKB1 expression in cells expressing aromatase were observed in the mammary epithelium from one of these individuals. Nuclear expression of the CRTC proteins, potent stimulators of aromatase and known to be inhibited by AMPK, was significantly correlated with aromatase.
CONCLUSIONS: Loss of heterozygosity of the STK11 gene leads to an increase in aromatase expression associated with an increase in CRTC nuclear localization, thereby providing a mechanism whereby PJS results in increased endogenous estrogens in affected males.

Jirásek V
[Digestive tract polyposes].
Vnitr Lek. 2013; 59(7):559-65 [PubMed] Related Publications
The article provides an overview of hereditary polyposis syndromes of the digestive tract and genetic mechanisms in greater detail. A brief summary of the basic symptoms of the condition, including extra gastrointestinal signs, is given. Significant diagnostic procedures are listed. The therapy for these disease conditions is either operative or endoscopic.

Zheng B, Pan J, Wang Y, et al.
Analysis of STK11 gene variant in five Chinese patients with Peutz-Jeghers syndrome.
Dig Dis Sci. 2013; 58(10):2868-72 [PubMed] Related Publications
BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous pigmentation. Germline mutation of a serine/threonine kinase 11(STK11) gene has been identified as a cause of PJS. In this study, we investigated the molecular basis of five Chinese PJS patients.
METHODS: Blood samples were collected from five unrelated Chinese PJS patients and their parents. The entire coding region of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing.
RESULTS: Three different frameshift mutations (c.519insTGTG, c.792_793insT, and c.334_335insC), all of which would cause truncation of the gene product, were found in three patients. One missense mutation (p.Ser307Thr) and one 3bp deletion mutation (c.228-230del CGT) were identified in the remaining two patients. All of the five investigated patients carried de novo mutations.
CONCLUSIONS: The results support that mutation of the LKB1 gene is a cause of PJS, and expand the spectrum of the STK11 gene mutations.

Udd L, Gao Y, Ristimäki AP, Mäkelä TP
N-methylnitrosourea aggravates gastrointestinal polyposis in Lkb1+/- mice.
Carcinogenesis. 2013; 34(10):2409-14 [PubMed] Related Publications
Peutz-Jeghers patients develop hamartomatous polyps and carcinomas of the gastrointestinal tract. Cyclooxygenase-2 accelerates polyp growth in Lkb1 (+/-) mice modelling Peutz-Jeghers polyposis. In this study, we aimed to evaluate the effect of the mutagenic carcinogen N-methylnitrosourea (MNU) on gastrointestinal tumourigenesis in Lkb1 (+/-) mice and to investigate the role of cyclooxygenase-2 on the tumourigenesis. We treated 40 Lkb1 (+/-) and 51 wild-type mice with MNU, 10 mice from both groups received the cyclooxygenase-2 inhibitor celecoxib. Carcinogen-treated Lkb1 (+/-) mice displayed worse survival (60%) than treated wild-type (100%, P = 0.028) or untreated Lkb1 (+/-) mice (92%, P = 0.045). Also, the gastrointestinal tumour burden was almost 10-fold higher in carcinogen-treated (2181 mm(3)) than in untreated (237 mm(3), P = 0.00045) Lkb1 (+/-) mice. Celecoxib was much less efficient in reducing tumourigenesis in MNU-treated mice (by 23%; 1686 mm(3)) than in untreated mice (76%; 58 mm(3)). Surprisingly, the increase in tumour burden in MNU-treated mice was not accompanied by consistent histological changes, with only a single focus of epithelial dysplasia noted. This study suggests that MNU promotes Peutz-Jeghers polyposis independently from the acceleration by cyclooxygenase-2.

Borun P, Bartkowiak A, Banasiewicz T, et al.
High Resolution Melting analysis as a rapid and efficient method of screening for small mutations in the STK11 gene in patients with Peutz-Jeghers syndrome.
BMC Med Genet. 2013; 14:58 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare hereditary syndrome characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation and increased risk of cancer in multiple internal organs. Depending on the studied population, its incidence has been estimated to range from 1:200 000 even up to 1:50 000 births. Being an autosomal disease, PJS is caused in most cases by mutations in the STK11 gene.
METHODS: The majority of causative DNA changes identified in patients with PJS are small mutations and, therefore, developing a method of their detection is a key aspect in the advancement of genetic diagnostics of PJS patients. We designed 13 pairs of primers, which amplify at the same temperature and enable examination of all coding exons of the STK11 gene by the HRM analysis.
RESULTS: In our group of 41 families with PJS small mutations of the STK11 gene were detected in 22 families (54%). In the remaining cases all of the coding exons were sequenced. However, this has not allowed to detect any additional mutations.
CONCLUSIONS: The developed methodology is a rapid and cost-effective screening tool for small mutations in PJS patients and makes it possible to detect all the STK11 gene sequence changes occurring in this group.

Vageli DP, Doukas SG, Markou A
Mismatch DNA repair mRNA expression profiles in oral melanin pigmentation lesion and hamartomatous polyp of a child with Peutz-Jeghers syndrome.
Pediatr Blood Cancer. 2013; 60(10):E116-7 [PubMed] Related Publications
Mismatch DNA repair (MMR) mRNA expression analysis was performed on a biopsy of oral mucosa melanin pigmentation lesion, a hamartomatous polyp and peripheral blood derived from a 12-year-old child with Peutz-Jeghers Syndrome (PJS). We present a deficient MMR system, in a PJS patient, which demonstrated low mRNA levels of hMSH6 and hPMS2 and an increasing MMR deficiency from the non-dysplastic lesion to hamartomatous polyp of PJS with a high risk of cancer.

Pan J, Li M, Jin Y, et al.
[Clinical characteristics and mutation analysis of the LKB1 gene in a Peutz-Jeghers syndrome pedigree].
Zhonghua Er Ke Za Zhi. 2013; 51(2):145-9 [PubMed] Related Publications
OBJECTIVE: To investigate clinical characteristics and mutation of the LKB1 gene in a Peutz-Jeghers syndrome (PJS) pedigree.
METHOD: Clinical data of a PJS family were analyzed and LKB1 gene mutation was detected by systematic screening with multiplex ligation-dependent probe amplification (MLPA) and DNA sequencing. Meanwhile, two hundred and fifty healthy adults were enrolled in this study and denaturing high performance liquid chromatography (PCR-DHPLC) was carried out to verify the mutation excluding polymorphism sites found in this family. Changes in protein structure and function caused by the mutated coding sequence was analyzed by SWISS-MODEL software.
RESULT: The proband had pigmented mucocutaneous lesions and multiple hamartomatous polyps in the gastrointestinal tract. There was no fragment deletion of LKB1 gene detected by MLPA. Among PJS family and 250 healthy adults, germline mutation c. 924G > C of LKB1 which cause Trp308Cys in protein sequence was identified only in the proband and another affected member. LKB1 protein activity could be reduced due to changes in LKB1 protein conformation structure by Trp308Cys.
CONCLUSION: Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterised by mucocutaneous pigmentation, multiple gastrointestinal hamartomatous polyps and heredofamilial nature. Gene identification and mutagen screening of LKB1 gene in all PJS patients and first degree relatives will contribute to a definite diagnosis and improve the life span of the family.

Korsse SE, Biermann K, Offerhaus GJ, et al.
Identification of molecular alterations in gastrointestinal carcinomas and dysplastic hamartomas in Peutz-Jeghers syndrome.
Carcinogenesis. 2013; 34(7):1611-9 [PubMed] Related Publications
Peutz-Jeghers syndrome (PJS) is caused by mutations in the LKB1 gene. It is characterized by gastrointestinal polyposis and an increased cancer risk, mainly in the gastrointestinal tract. Mechanisms of PJS-associated carcinogenesis are unclear. We investigated the involvement of candidate genes and molecular pathways in PJS-associated gastrointestinal cancers and dysplastic hamartomas. Cases were selected from the Dutch PJS cohort. Available tissue was immunostained for phospho-S6, β-catenin, P53 and SMAD4. DNA was isolated from carcinoma tissue and dysplastic and non-dysplastic areas of hamartomas specifically. Mutation analyses were done for BRAF, KRAS and P53, and loss of heterozygosity (LOH) analyses for LKB1 and P53. Twenty-four of 144 patients (17%) developed 26 gastrointestinal malignancies at a median age of 49 years (interquartile range: 35-60). Eleven of 792 hamartomas (1.4%) of 9 patients were classified as dysplastic. LOH of LKB1 was detected in three of six (50%) carcinomas and in the dysplastic part of three of five (60%) hamartomas. Aberrant P53 expression was observed in 8 of 15 (53%) carcinomas. Six carcinomas with P53 overexpression harboured a P53 mutation, with loss of the remaining wild-type allele in four. Two hamartomas showing P53 overexpression in high-grade dysplastic foci harboured a P53 mutation with LOH. Loss of nuclear SMAD4 was observed in high-grade dysplastic foci of two of four (50%) hamartomas, in contrast to low-grade dysplastic foci (0/4) and non-dysplastic epithelium. Our findings suggest a role for mutant P53 in PJS-associated gastrointestinal carcinogenesis. Inactivation of transforming growth factor-β/bone morphogenetic protein signalling and complete loss of LKB1 might be involved in dysplastic transformation of gastrointestinal hamartomas specifically.

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