Cause Of Peutz-Jeghers Syndrome Research Articles

Mutations of the STK11 and FHIT genes among patients with Peutz-Jeghers syndrome

To correlate the clinical characteristics with mutations of the STK11 and FHIT genes in 16 patients with Peutz-Jeghers syndrome (PJS). Potential mutations in the coding regions and flanking sequences of the STK11 and FHIT genes were detected with PCR and Sanger sequencing. 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%. 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.

Clinical characteristics and STK11 gene mutations in Chinese children with Peutz-Jeghers syndrome.

BackgroundPeutz-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.MethodsThirteen 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.ResultsThe 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.ConclusionsThe 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.

Downregulation of LKB1 suppresses Stat3 activity to promote the proliferation of esophageal carcinoma cells

The tumor suppressor liver kinase B1 (LKB1) encodes a serine/threonine kinase. The defect in LKB1 is the primary cause of Peutz-Jeghers syndrome (PJS). Inactivation of LKB1 by mutations or loss of LKB1 expression is associated with ovarian, lung and pancreatic cancer; however, the correlation between LKB1 and esophageal carcinoma remains unknown. Thus, quantitative PCR was performed to determine the clinical significance of LKB1 expression in 60 cases of esophageal cancer and its adjacent normal epithelium. LKB1 expression was observed to significantly downregulate the accompanying cancer progression, which was verified at the protein level by western blot analysis. Furthermore, the phosphorylated signal transducer and activator of transcription 3 (Stat3) level is reversibly associated with LKB1 expression. To determine the function of LKB1 in esophageal cancer, LKB1 expression is induced in TE1 esophageal cancer cells. The results show that LKB1 overexpression suppresses the proliferation of TE1 cells, downregulates the expression of cyclin D1 and Myc and represses Stat3 phosphorylation. Suppression of cell proliferation and cyclin D1 expression by LKB1 is fully inhibited by constitutively active Stat3C coexpression, suggesting that LKB1 inhibits esophageal cancer cell proliferation through suppression of Stat3 transaction. In conclusion, downregulation of LKB1 expression suppresses Stat3 activity that may promote tumor growth during esophageal cancer progression.

Analysis of STK11 Gene Variant in Five Chinese Patients with Peutz-Jeghers Syndrome

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. 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. 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. The results support that mutation of the LKB1 gene is a cause of PJS, and expand the spectrum of the STK11 gene mutations.

A Case of Peutz-Jeghers Syndrome in Association with Sarcoidosis

Purpose: Case Report: Our case involves a 60 year old European gentleman with a past medical history of steroid-dependent sarcoid, HTN, colon cancer and Peutz-Jeghers syndrome (PJS) who is routinely seen in our outpatient office. A routine colonoscopy for CRC screening at the age of 50 found a colonic malignancy which necessitated a sigmoid colectomy. A recurrence of his disease two years later resulted in a left hemicolectomy. At the age of 56, after a negative EGD and colonoscopy, the patient was sent to our institution for further evaluation of microcytic anemia with guaic positive stools. A capsule endoscopy revealed multiple large polyps extending from the 2nd portion of the duodenum to the distal jejunum. The patient then underwent his first DBE with antegrade approach and removal of 15 polyps. However, not all the polyps could be safely removed. The patient subsequently underwent laparoscopic resection of his small bowel. Though the patient did not have the expected findings of a history of intussusceptions, SBO or abdominal pain, close inspection of his oral cavity revealed melanin deposition on his oral mucosa and a faint mucocutaneous pigmentation. With the aforementioned clinical presentation and pathological findings, the patient was given a diagnosis of PJS. In regards to his sarcoid, the patient was diagnosed at the age of 30 when he presented to his PCP with enlarging plaques. Fifteen years later, he developed SOB and pulmonary sarcoidosis was confirmed. We have continued to be involved in his care for management and surveillance of his PJS and see him twice yearly. Discussion: The prevalence of PJS is estimated to be between 1/60,000-1/300,000. Similarly rare, the overall prevalence of sarcoidosis in Caucasian patients in the United States has been noted to be less than 10/100,000 patients. As such, the possibility of both rare diseases independently occurring in a single patient would be exceedingly unlikely. For this reason, we postulate the presence of a common genetic or biochemical pathway. PJS most commonly manifests as multiple gastrointestinal hamartomatous polyps and hyperpigmented mucosal lesions with a predisposition to developing malignancy. The underlying cause of PJS is a germ line mutation in a gene encoding the serine threonine kinase tumor suppressor STK11/LKB1 on band 19p13.3. Though the genetics of sarcoid continue to be a mystery, an association with the HLA-DR allele on band 6p21.31 has been identified in certain populations. We postulate a possible connection between these two rare genetic entities and note that further genetic and population studies may be warranted.

One Novel Deletion and One Splicing Mutation of the LKB1 Gene in Two Chinese Patients with Peutz–Jeghers Syndrome

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.

Novel mutations in the STK11 gene in Thai patients withPeutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS), a rare autosomal dominant inherited disorder, is characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation. Patients with this syndrome have a predisposition to a variety of cancers in multiple organs. Mutations in the serine/threonine kinase 11 (STK11) gene have been identified as a major cause of PJS. Here we present the clinical and molecular findings of two unrelated Thai individuals with PJS. Mutation analysis by Polymerase Chain Reaction-sequencing of the entire coding region of STK11 revealed two potentially pathogenic mutations. One harbored a single nucleotide deletion (c.182delG) in exon 1 resulting in a frameshift leading to premature termination at codon 63 (p.Gly61AlafsX63). The other carried an in-frame 9-base-pair (bp) deletion in exon 7, c.907_915del9 (p.Ile303_Gln305del). Both deletions were de novo and have never been previously described. This study has expanded the genotypic spectrum of the STK11 gene.

Genetic defects underlying Peutz–Jeghers syndrome (PJS) and exclusion of the polarity‐associated MARK/Par1 gene family as potential PJS candidates

LKB1/STK11 germline inactivations are identified in the majority (66-94%) of Peutz-Jeghers syndrome (PJS) patients. Therefore, defects in other genes or so far unidentified ways of LKB1 inactivation may cause PJS. The genes encoding the MARK proteins, homologues of the Par1 polarity protein that associates with Par4/Lkb1, were analyzed in this study because of their link to LKB1 and cell polarity. The genetic defect underlying PJS was determined through analysis of both LKB1 and all four MARK genes. LKB1 point mutations and small deletions were identified in 18 of 23 PJS families using direct sequencing and multiplex ligation-dependent probe amplification analysis identified exon deletions in 3 of 23 families. In total, 91% of the studied families showed LKB1 inactivation. Furthermore, a MARK1, MARK2, MARK3 and MARK4 mutation analysis and an MARK4 quantitative multiplex polymerase chain reaction analysis to identify exon deletions on another eight PJS families without identified LKB1 germline mutation did not identify mutations in the MARK genes. LKB1 defects are the major cause of PJS and genes of the MARK family do not represent alternative PJS genes. Other mechanisms of inactivation of LKB1 may cause PJS in the remaining families.

LKB1 gene mutations in Japanese lung cancer patients

Mutation of the LKB1 gene (also known as STK11) is regarded as a cause of Peutz-Jeghers syndrome. In Caucasian patients, LKB1 somatic mutations occur in approximately one-third of lung adenocarcinomas. The aim of the present study was to examine the LKB1 gene in Japanese patients with lung cancer and to evaluate its clinical and pathological implications. We sequenced the LKB1 gene in 22 lung cancer cell lines and 100 Japanese patients with lung cancer (including 81 adenocarcinomas, 14 squamous cell carcinomas and five other histological types) who had undergone curative pulmonary resection. We also determined expression levels of the LKB1 gene by quantitative real-time reverse transcription-polymerase chain reaction and correlated these results with the clinical and pathological features of patients. Among the 22 cell lines, four had mutations and three of these were in adenocarcinoma cells. Of 100 primary lung cancers, only three had LKB1 gene mutations (3%). All of them were male smokers with adenocarcinomas. Hence, when confined to this subset of patients, the mutation frequency was 9% (3/33). No significant correlation was observed between the expression level of LKB1 and patient clinicopathological features. In conclusion, LKB1 gene mutations were relatively rare in Japanese patients with lung cancer compared with Caucasian patients. LKB1 gene mutations appear to be frequent in male, smoking patients of Caucasian origin, in contrast to EGFR or HER2 mutations that are frequent in non-smoking, female patients of Asian origin.

Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma.

Mutations in LKB1/STK11, a gene mapping to chromosome 19p13.3 and encoding a widely expressed serine/threonine kinase, were recently identified as the cause of Peutz-Jeghers syndrome. Despite the hamartomatous polyps and increased cancer risk associated with this syndrome, somatic alterations in LKB1/STK11 have not been identified in human tumours. Prompted by another feature of the syndrome, lentigines of the lips and oral mucosa, we evaluated the status of LKB1/STK11 expression, deletion, and mutation in cell lines and tumour samples from 35 patients with sporadic malignant melanoma. Two somatic mutations were identified, a nonsense mutation (Glu170Stop) causing exon skipping and intron retention, and a missense mutation (Asp194Tyr) affecting an invariant residue in the catalytic subunit of LKB1/STK11. Our data suggest that LKB1/STK11 may contribute to tumorigenesis in a small fraction of malignant melanomas.

Peutz-Jeghers syndrome: molecular analysis of a three-generation kindred with a novel defect in the serine threonine kinase gene STK11

The Peutz-Jeghers syndrome, phenotypically characterized by mucocutaneous pigmentation and hamartomatous polyposis, is an autosomal dominant disease with variable expression and incomplete penetrance. Moreover, affected patients are at increased risk for gastrointestinal and other malignancies. Recently, a mutated gene encoding abnormal forms of the novel serine threonine kinase STK11 has been identified as a genetic cause of Peutz-Jeghers syndrome. Here, we report the molecular analysis of the STK11 gene in a patient with Peutz-Jeghers syndrome, which in exon 1 revealed a guanine (G) insertion in the 5 G repeat of codons 51–53. The insertion leads to a frameshift with a premature TGA stop codon 324 bp downstream in codon 162, predicting the expression of a truncated protein without kinase activity. This heterozygous germline mutation was also found in the affected father and in one affected sister of the index patient, but not in any phenotypically unaffected family member or in unrelated control subjects. In DNA isolated from microdissected hamartomatous polyps of the index patient, exon 1 of the STK11 gene could not be amplified suggesting that both alleles of STK11 exon 1 were lost in the hamartomatous polyps. Identification of a STK11 gene mutation in an index patient offers the possibility of a predictive diagnosis, and initiation of specific screening programs in the genetically affected kindred.