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 08 August, 2015 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

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Useful links (6 links)

Latest Publications

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] 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.

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.

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.

Resta N, Pierannunzio D, Lenato GM, et al.
Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study.
Dig Liver Dis. 2013; 45(7):606-11 [PubMed] Related Publications
BACKGROUND: Germline mutations in the STK11/LKB1 gene cause Peutz-Jeghers syndrome, an autosomal-dominantly inherited condition characterized by mucocutaneous pigmentation, hamartomatous gastrointestinal polyposis, and an increased risk for various malignancies. We here report the results of the first Italian collaborative study on Peutz-Jeghers syndrome.
AIMS: To assess cancer risks in a large homogenous cohort of patients with Peutz-Jeghers syndrome, carrying, in large majority, an identified STK11/LKB1 mutation.
METHODS: One-hundred and nineteen patients with Peutz-Jeghers syndrome, ascertained in sixteen different Italian centres, were enrolled in a retrospective cohort study. Relative and cumulative cancer risks and genotype-phenotype correlations were evaluated.
RESULTS: 36 malignant tumours were found in 31/119 (29 STK11/LKB1 mutation carriers) patients. The mean age at first cancer diagnosis was 41 years. The relative overall cancer risk was 15.1 with a significantly higher risk (p < 0.001) in females (22.0) than in males (8.6). Highly increased relative risks were present for gastrointestinal (126.2) and gynaecological cancers (27.7), in particular for pancreatic (139.7) and cervical cancer (55.6). The Kaplan-Meier estimates for overall cumulative cancer risks were 20%, 43%, 71%, and 89%, at age 40, 50, 60 and 65 years, respectively.
CONCLUSION: Peutz-Jeghers syndrome entails markedly elevated cancer risks, mainly for pancreatic and cervical cancers. This study provides a helpful reference for improving current surveillance protocols.

Korsse SE, van Leerdam ME, Dekker E
[Peutz-Jeghers syndrome].
Ned Tijdschr Tandheelkd. 2013; 120(1):12-6 [PubMed] Related Publications
Peutz-Jeghers syndrome is a rare, autosomal dominant inherited disorder, which is characterized by mucocutaneous pigmentations, gastrointestinal polyposis and an increased risk of cancer. It is caused by germline mutations in the LKB1 tumour suppressor gene, as a result of which hamartomatous polyps can develop already at an early age, which may cause various complications, including abdominal pain, anaemia, and acute intestinal obstruction. Patients have an increased risk of developing cancer, in the gastroinstestinal tract and in other organs. As a result of the risk of complications related to the hamartomatous polyps and the increased risk of cancer, the medical management mainly consists of surveillance. Upper and lower endoscopies are recommended for surveillance, the small bowel should be investigated with magnetic resonance imaging and regular inspection of the pancreas with imaging techniques is recommended. Women are advised to seek regular breast- and gynaecological screening from an early age. The pathogenesis of hamartomas and carcinomas is unclear. More insight into the molecular background might lead to targeted medicinal therapies for patients with this syndrome.

Korsse SE, Peppelenbosch MP, Smits R, van Veelen W
GNAS is not involved in gastrointestinal tumour formation in Peutz-Jeghers syndrome.
Fam Cancer. 2013; 12(3):581-2 [PubMed] Related Publications
Peutz-Jeghers syndrome (PJS), caused by germ-line mutations in LKB1, is characterized by the development of hamartomatous polyps in the gastrointestinal (GI) tract. McCune Albright syndrome (MAS), caused by somatic activating mutations in GNAS, presents with cutaneous, skeletal, and endocrine manifestations. Recently, hamartomatous GI polyps with histological features similar to those in PJS were observed in MAS patients, suggesting a role for GNAS in the pathogenesis of PJS. This study reports the first somatic GNAS mutation analysis in GI tumours of PJS patients. No mutations were observed, suggesting that GNAS is not involved in the pathogenesis of GI tumours in PJS.

Scollon S, McWalter K, Abe K, et al.
Haploinsufficiency of STK11 and neighboring genes cause a contiguous gene syndrome including Peutz-Jeghers phenotype.
Am J Med Genet A. 2012; 158A(11):2959-62 [PubMed] Related Publications
We report on clinical and molecular findings of a 15-year-old female referred to our genetics clinic for a diagnostic evaluation due to mild developmental delay, submucosal cleft palate, and seizure disorder. Chromosomal microarray technology revealed a cancer predisposition due to a terminal deletion on chromosome 19p that includes the tumor suppressor gene STK11. In addition to abnormal lip pigmentation on exam, further diagnostic workup with upper and lower gastrointestinal screening confirmed polyps consistent with Peutz-Jeghers syndrome. The purpose of this study is to present a full clinical description of a patient with a rare 19p13.3 chromosomal deletion and review the current literature of this newly emerging contiguous gene deletion syndrome. It also supports the screening for complications of Peutz-Jeghers syndrome in all patients with this deletion.

Chen C, Zhang X, Wang F, et al.
One novel deletion and one splicing mutation of the LKB1 gene in two Chinese patients with Peutz-Jeghers syndrome.
DNA Cell Biol. 2012; 31(10):1535-40 [PubMed] Related Publications
Peutz-Jeghers syndrome (PJS) is an uncommon autosomal dominant inherited disease, characterized by the occurrence of gastrointestinal hamartomatous polyps and pigmentation of the lips, buccal mucosa, and digits. Patients with PJS have a significant risk for developing tumors in multiple organs. Germline mutation of the LKB1 gene, which encodes a serine/threonine kinase that acts as a tumor suppressor, has been identified as a cause of PJS. The current study included two Chinese PJS probands and their available family members, as well as 200 unrelated healthy controls for comparison. Genomic DNA was extracted from the peripheral blood of these subjects. The nine coding exons and flanking introns of the LKB1 gene in the two probands and their family members were amplified by polymerase chain reaction (PCR) and then directly sequenced. Mutations identified in the patients were checked in the 200 healthy controls by PCR and denaturing high-performance liquid chromatography. Total RNA was extracted from the patient who was found to have a dubious splice site mutation and his available family members. Reverse transcription PCR was performed to identify the abnormal splicing caused by the splice site mutation. Two types of mutations were detected in the two PJS families. One type was a previously unreported 30-base-pair deletion in exon 4, and the other was an intron mutation that affected splicing. None of the 200 controls had either of these two types of mutations. The results provide support that mutation of the LKB1 gene is a cause of PJS, and expand the spectrum of LKB1 gene mutations.

Orellana P, López-Köstner F, Heine C, et al.
Large deletions and splicing-site mutations in the STK11 gene in Peutz-Jeghers Chilean families.
Clin Genet. 2013; 83(4):365-9 [PubMed] Related Publications
Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by mucocutaneous melanocytic macules, gastrointestinal hamartomatous polyposis and an increased risk of various neoplasms. Germline mutations in the serine/threonine kinase 11 (STK11) gene have been identified as a cause for PJS. The aim of this study was to characterize the genotype of Chilean PJS patients. Mutation screening of 13 patients from eight PJS families was performed using a single strand conformation polymorphism analysis, DNA sequencing and multiplex ligation-dependent probe amplification assay. The breakpoints of the genomic rearrangements were assessed by a long-range polymerase chain reaction and sequencing. The results revealed the existence of seven different pathogenic mutations in STK11 gene in seven unrelated families, including three point mutations and four large genomic deletions. Three of these point mutations (43%, 3/7) may be considered as novel. Our results showed that a germline mutation is present in STK11 in 88% of probands fulfilling the diagnostic criteria of PJS. In this study, the combination of two different experimental approaches in the screening of the STK11 in PJS, led to a higher percentage of mutation detection.

Zhao X, Li Y, Ling Y, et al.
[Mutation analysis of STK11 gene coding region for 20 Chinese patients with Peutz-Jeghers syndrome].
Nan Fang Yi Ke Da Xue Xue Bao. 2012; 32(4):511-4 [PubMed] Related Publications
OBJECTIVE: To analyze the sequence of STK11 gene coding region in 20 patients with Peutz-Jeghers syndrome and identify the point mutations in STK11 gene associated with the occurrence of the disease.
METHODS: Blood samples were collected from 20 inpatients with Peutz-Jeghers syndrome treated in our center between January 2009 and October 2010. The sequence of STK11 gene coding region was analyzed using PCR and DNA sequencing and compared with the normal sequence of STK11 gene.
RESULTS: Of the 20 patients with Peutz-Jeghers syndrome, 14 showed STK11 gene mutations in the coding region, including 1 patient having two mutations and 13 patients with a single mutation site. In one case, sequence analysis of the STK11 gene identified a novel type of STK11 germline mutation, in which the cytosine (C)460 was substituted by guanine (G) in exon 3 to result in a new amino acid at codon 154. Four patients from 2 families were found to have a common mutation. The remaining 6 patients were not found to have mutations in STK11 gene coding region.
CONCLUSION: Mutations of STK11 gene is a major cause of Peutz-Jeghers syndrome. The missense mutation of 460 C→G in exon 3 of STK11 gene is a novel mutation associated with Peutz-Jeghers syndrome.

Chen CY, Zhang XM, Wang FY, et al.
[Mutation screening of LKB1 gene in familial Peutz-Jeghers syndrome patients].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2012; 29(2):121-5 [PubMed] Related Publications
OBJECTIVE: To screen for potential mutations of LKB1 gene in Chinese familial Peutz-Jeghers syndrome (PJS) patients and analyze their clinical manifestations.
METHODS: Eleven PJS families were collected and genomic DNA of peripheral blood was extracted. Typically mucosal pigmentation and hamartomatous polyps were present in all 11 probands. Mutation screening of the probands were carried out by PCR and direct sequencing. Two hundred and fifty healthy adults were enrolled as normal controls, for whom genomic DNA of peripheral blood was also extracted. PCR-denaturing high performance liquid chromatography was carried out to verify the mutation identified in the patients.
RESULTS: Nine germline mutations were identified in eight PJS patients, which included 7 point mutations, 1 deletion and 1 insertion. Among these, 4 were considered to be pathogenic, of which 2 were de novel, 4 were considered to be polymorphism, and 1 was uncertain.
CONCLUSION: LKB1 gene mutations with pathogenic effect are a common cause of familial PJS in Chinese patients. Most mutations are point mutations.

Wang Z, Chen Y, Wu B, et al.
A novel mutation in STK11 gene is associated with Peutz-Jeghers syndrome in Chinese patients.
BMC Med Genet. 2011; 12:161 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Peutz-Jeghers syndrome (PJS) is caused by mutations in the tumor suppressor gene, STK11, and is characterized by gastrointestinal hamartomas, melanin spots on the lips, and an increased risk of developing cancer.
METHODS: Blood samples were collected from two unrelated Chinese PJS families totaling 20 individuals (9 male and 11 females), including 6 PJS patients. The entire coding region of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing.
RESULTS: A novel mutation, c.904C > T, in exon 7 was identified in both families. A C > T substitution changed codon 302 from CAG (glutamine) to TAG (stop), truncating the STK11 protein, thus leading to the partial loss of the kinase domain and complete loss of the α-helix C-terminus. Furthermore, one PJS patient from each family was diagnosed with a visceral cancer, a colon cancer and a liver cancer respectively.
CONCLUSION: We predict that this novel mutation, p.Q302X, is most likely responsible for development of the PJS phenotype and may even contribute to malignancy.

Liu WL, Li F, He ZX, et al.
Identification of a novel de novo STK11 mutation in a Chinese child with Peutz-Jeghers syndrome.
J Int Med Res. 2011; 39(5):2033-8 [PubMed] Related Publications
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder characterized by gastrointestinal polyposis and mucocutaneous pigmentation. PJS patients have an increased risk of cancer in multiple locations. Germ-line mutations in the STK11 gene have been found to be responsible for most PJS cases. DNA samples were obtained from a Chinese child with PJS, his clinically unaffected parents and 50 unrelated normal individuals, and the exons and flanking intronic sequences of the STK11 gene were analysed by polymerase chain reaction and direct sequencing. A novel de novo mutation (c.698_699insG; F234LfsX3) was identified in exon 5 of STK11, that resulted in a translational frameshift leading to termination at codon 236. This mutation was not found in the parents or unrelated individuals. These results enlarge the genotypic spectrum of STK11, particularly with regard to early onset, as observed in the present sporadic PJS case. This study may have important future implications for precise genotype-phenotype correlation research.

Langner C
[Non-serrated precursor lesions of colorectal tumours].
Pathologe. 2011; 32 Suppl 2:206-10 [PubMed] Related Publications
Non-serrated precursor lesions of colorectal tumours include conventional adenomas (tubular, tubulovillous and villous), inflammatory bowel disease-associated dysplasia (intraepithelial neoplasia), and hamartoma-associated dysplasia. This short review summarizes the current literature on the adenoma-carcinoma sequence, focusing on colonic stem cells and functional crypt organization, patterns of stem cell division, niche succession and clonal conversion in the formation of a monocryptal adenoma. The process of clonal interaction between neighboring crypts as well as the development of large monoclonal adenomas from small polyclonal precursor lesions is discussed in detail. Finally, the molecular pathogenesis as well as the clinical significance of inflammatory bowel disease- and hamartoma-associated carcinogenesis is addressed.

van Lier MG, Korsse SE, Mathus-Vliegen EM, et al.
Peutz-Jeghers syndrome and family planning: the attitude towards prenatal diagnosis and pre-implantation genetic diagnosis.
Eur J Hum Genet. 2012; 20(2):236-9 [PubMed] Free Access to Full Article Related Publications
Peutz-Jeghers syndrome (PJS) is a hereditary disorder caused by LKB1 gene mutations, and is associated with considerable morbidity and decreased life expectancy. This study was conducted to assess the attitude of PJS patients towards family planning, prenatal diagnosis (PND) and pregnancy termination, and pre-implantation genetic diagnosis (PGD). In a cross-sectional study, 61 adult PJS patients were asked to complete a questionnaire concerning genetic testing, family planning, PND and PGD. The questionnaire was completed by 52 patients (85% response rate, 44% males) with a median age of 44 (range 18-74) years. A total of 37 (71%) respondents had undergone genetic testing. In all, 24 respondents (46%, 75% males) had children. A total of 15 (29%) respondents reported that their diagnosis of PJS had influenced their decisions regarding family planning, including 10 patients (19%, 9/10 females) who did not want to have children because of their disease. Termination of pregnancy after PND in case of a foetus with PJS was considered 'acceptable' for 15% of the respondents, whereas 52% considered PGD acceptable. In conclusion, the diagnosis of PJS influences the decisions regarding family planning in one third of PJS patients, especially in women. Most patients have a negative attitude towards pregnancy termination after PND, while PGD in case of PJS is judged more acceptable. These results emphasise the importance of discussing aspects regarding family planning with PJS patients, including PND and PGD.

Osoegawa A, Kometani T, Nosaki K, et al.
LKB1 mutations frequently detected in mucinous bronchioloalveolar carcinoma.
Jpn J Clin Oncol. 2011; 41(9):1132-7 [PubMed] Related Publications
OBJECTIVE: LKB1 mutations are common in patients with Peutz-Jeghers syndrome, which is characterized by mucocutaneous pigmentation, intestinal polyps and a high incidence of cancers at variable sites. This study investigated the status of the LKB1 gene in mucinous bronchioloalveolar carcinoma with or without Peutz-Jeghers syndrome.
METHODS: Three mucinous bronchioloalveolar carcinoma tumors from two Peutz-Jeghers syndrome patients and seven tumors from sporadic mucinous bronchioloalveolar carcinoma patients were collected by surgery between 2002 and 2008, and high molecular weight genomic DNA was extracted from them. The nucleotide sequences in exons 1-9 of LKB1 were determined by genomic polymerase chain reaction-direct sequencing. The loss of heterozygosity was analyzed by high-resolution fluorescent microsatellite analysis using two microsatellite markers that encompass the LKB1 locus, D19S886 and D19S565. The mutations of KRAS, EGFR and p53 were also evaluated.
RESULTS: The germline mutation of LKB1 in the Peutz-Jeghers syndrome patients was identified as G215D by analyzing genomic DNA from normal lung tissue specimens. Furthermore, two of the three mucinous bronchioloalveolar carcinomas from these Peutz-Jeghers syndrome patients exhibited additional somatic mutations. On the other hand, four of seven sporadic 'non-Peutz-Jeghers syndrome' mucinous bronchioloalveolar carcinomas had LKB1 mutations. Loss of heterozygosity analyses revealed allelic loss in two tumors with LKB1 mutations. As a result, 70% of the mucinous bronchioloalveolar carcinomas exhibited LKB1 mutations. KRAS, EGFR and p53 mutations were mutually exclusive and observed in four, two and one tumors, respectively. Among them, five mutations occurred concomitantly with LKB1 mutations.
CONCLUSIONS: The relatively high frequency of LKB1 mutations in mucinous bronchioloalveolar carcinoma patients may therefore suggest its involvement in lung carcinogenesis, at least in mucinous bronchioloalveolar carcinoma.

Lodish MB, Stratakis CA
The differential diagnosis of familial lentiginosis syndromes.
Fam Cancer. 2011; 10(3):481-90 [PubMed] Free Access to Full Article Related Publications
Cutaneous markers of systemic disease are vital for clinicians to recognize. This chapter outlines familial lentiginosis syndromes that include Peutz-Jeghers syndrome, Carney Complex, the PTEN hamartomatous syndromes, and LEOPARD/Noonan syndrome. The inheritance of these syndromes is autosomal dominant; they also share characteristic skin findings that offer a clue to their recognition and treatment. We will discuss the clinical presentation of these disorders, with a focus on the dermatological manifestations, and will provide an update on the molecular mechanisms involved. Recognition of cutaneous markers associated with these rare familial cancer syndromes provides the opportunity to pursue early surveillance for malignancies, as well as genetic counseling.

Liu L, Du X, Nie J
A novel de novo mutation in LKB1 gene in a Chinese Peutz Jeghers syndrome patient significantly diminished p53 activity.
Clin Res Hepatol Gastroenterol. 2011; 35(3):221-6 [PubMed] Related Publications
Peutz Jeghers syndrome (PJS) is an autosomal dominant disease caused by mutations in the LKB1 gene. We screened for the LKB1 gene mutation in a Chinese PJS patient. Sequence analysis of LKB1 exons showed that there was a novel de novo mis-sense mutation of codon 16 (GAG to GGG) in exon 1 in LKB1 gene in the Chinese PJS patient. Furthermore, we observed that wild type LKB1 expression increased p53 activity, while LKB1 A47G mutation had no such effect on p53 activity, indicating that the mis-sense variant of LKB1 influenced the p53 activation function of LKB1 protein. In addition, real-time RT-PCR analysis revealed that the expression levels of p53 downstream targets were significantly diminished in affected PJS patient compared with those in unaffected parents, further confirming the roles of LKB1 and p53 in PJS pathogenesis. Therefore, a novel PJS associated LKB1 gene mutation is provided, and the roles of LKB1 and p53 in PJS pathogenesis is validated in this research.

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