STK11 genotyping and cancer risk in Peutz-Jeghers syndrome.
Ontology highlight
ABSTRACT:
SUBMITTER: Schumacher V
PROVIDER: S-EPMC1736065 | biostudies-literature | 2005 May
REPOSITORIES: biostudies-literature
Publications
STK11 genotyping and cancer risk in Peutz-Jeghers syndrome.
Schumacher V V Vogel T T Leube B B Driemel C C Goecke T T Möslein G G Royer-Pokora B B
Journal of medical genetics 20050501 5
Similar Datasets
Project description:BackgroundPeutz-Jeghers syndrome (PJS) is caused by germline STK11 mutations and characterised by gastrointestinal polyposis. Although small bowel intussusception is a recognised complication of PJS, risk varies between patients.ObjectiveTo analyse the time to onset of intussusception in a large series of PJS probands.MethodsSTK11 mutation status was evaluated in 225 PJS probands and medical histories of the patients reviewed.Results135 (60%) of the probands possessed a germline STK11 mutation; 109 (48%) probands had a history of intussusception at a median age of 15.0 years but with wide variability (range 3.7 to 45.4 years). Median time to onset of intussusception was not significantly different between those with identified mutations and those with no mutation detected, at 14.7 years and 16.4 years, respectively (log-rank test of difference, chi(2) = 0.58, with 1df; p = 0.45). Similarly no differences were observed between patient groups on the basis of the type or site of STK11 mutation.ConclusionsThe risk of intussusception in PJS is not influenced by STK11 mutation status.
| S-EPMC2564597 | biostudies-literature
Project description:Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz-Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27-73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype-phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.
| S-EPMC2394252 | biostudies-literature
Project description:BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disease characterized by gastrointestinal hamartomatous polyposis and mucocutaneous pigmentation. The genetic predisposition for PJS has been shown to be associated with germline mutations in the STK11/LKB1 tumor suppressor gene. The aim of the present study was to characterize Hungarian PJS patients with respect to germline mutation in STK11/LKB1 and their association to disease phenotype. METHODS: Mutation screening of 21 patients from 13 PJS families were performed using direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). Comparative semi-quantitative sequencing was applied to investigate the mRNA-level effects of nonsense and splice-affecting mutations. RESULTS: Thirteen different pathogenic mutations in STK11, including a high frequency of large genomic deletions (38%, 5/13), were identified in the 13 unrelated families studied. One of these deletions also affects two neighboring genes (SBNO2 and GPX4), located upstream of STK11, with a possible modifier effect. The majority of the point mutations (88%, 7/8) can be considered novel. Quantification of the STK11 transcript at the mRNA-level revealed that the expression of alleles carrying a nonsense or frameshift mutation was reduced to 30-70% of that of the wild type allele. Mutations affecting splice-sites around exon 2 displayed an mRNA processing pattern indicative of co-regulated splicing of exons 2 and 3. CONCLUSIONS: A combination of sensitive techniques may assure a high (100%) STK11 mutation detection frequency in PJS families. Characterization of mutations at mRNA level may give a deeper insight into the molecular consequences of the pathogenic mutations than predictions made solely at the genomic level.
| S-EPMC3012662 | biostudies-literature
Project description:BackgroundPeutz-Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro-facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients.MethodsHere we report the comprehensive mutational analysis of STK11 in 38 PJS probands applying conventional PCR based mutation detection methods and the recently introduced MLPA (multiplex ligation dependent probe amplification) technique developed for the identification of exonic deletions/duplications.ResultsNineteen of 38 probands (50%) had detectable point mutations or small scale deletions/insertions and six probands (16%) had genomic deletions encompassing one or more STK11 exons.ConclusionsThese findings demonstrate that exonic STK11 deletions are a common cause of PJS and provide a strong rationale for conducting a primary screen for such mutations in patients.
| S-EPMC2563227 | biostudies-literature
Project description: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.
| S-EPMC4659168 | biostudies-literature
Project description:BackgroundPeutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous hyperpigmentation, and an increased risk of cancer. Mutations in the serine-threonine kinase 11 gene (SKT11) are the major cause of PJS.Case presentationBlood samples were collected from six PJS families including eight patients. Mutation screening of STK11 gene was performed in these six families by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) assay. Three novel mutations (c.721G > C, c.645_726del82, and del(exon2-5)) and three recurrent mutations (c.752G > A, c.545 T > C and del(exon1)) in STK11 were detected in six Chinese PJS families. Genotype-phenotype correlations suggested that truncating mutations trend to result in severe complications.ConclusionThese findings broaden the mutation spectrum of the STK11 gene and would help clinicians and genetic counselors provide better clinical surveillance for PJS patients, especially for ones carrying truncating mutation.
| S-EPMC5100203 | biostudies-literature
Project description: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.
| S-EPMC2776867 | biostudies-literature
Project description:BackgroundPeutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary disease characterized by mucocutaneous pigmentation and gastrointestinal hamartomatous polyposis. The germline mutations in the serine/threonine kinase 11 (STK11) gene have been shown to be associated with the disease. Individuals with PJS are at increased risk for development of various neoplasms. The aim of the present study was to characterize the genotype and phenotype of Czech patients with PJS.MethodsWe examined genomic DNA of 8 individuals from five Czech families by sequencing analysis of STK11 gene, covering its promotor region, the entire coding region and the splice-site boundaries, and by multiplex ligation-dependent probe amplification (MLPA) assay designed for the identification of large exonic deletions or duplications of STK11 gene.ResultsWe found pathogenic mutations in STK11 gene in two families fulfilling the diagnostic criteria of PJS and in one of three sporadic cases not complying with the criteria. The patient with the frameshift mutation in STK11 gene developed aggressive gastric cancer. No other studied proband has developed a carcinoma so far.ConclusionOur results showed that a germline mutation of STK11 gene can be found not only in probands fulfilling the PJS diagnostic criteria, but also in some sporadic cases not complying with the criteria. Moreover, we observed a new case of aggressive gastric cancer in a young patient with a frameshift mutation of STK11 gene.
| S-EPMC2726128 | biostudies-literature
Project description:BackgroundPeutz-Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disease resulting in multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation, and an increased risk of various types of cancer, and is caused by variations in the serine/threonine protein kinase STK11 (LKB1).MethodsSTK11 gene variations were identified by analyzing STK11 cDNA and genomic DNA. Minigenes carrying the wild-type and mutant sequences were subjected to in vitro splicing assay to dissect the features of these mutations. The different distribution of wild-type and mutant protein in cells were tested by Immunofluorescence assays and the functional analysis of the variation were performed using Western blot.ResultsA novel heterozygous splice-acceptor site variation (c.921-2 A>C) in intron 7 of the STK11 gene which is co-segregates with the PJS phenotypes in the proband and all the affected family members and three previously reported variations (c.180C>G, c.580G>A, c.787_790del) were identified in the four families. The c.921-2 A>C substitution resulted in the inactivation of a splice site and the utilization of a cryptic splice acceptor site surrounding exon 8, generating three different aberrant RNA transcripts, leading to frameshift translation and protein truncation. The results of minigenes indicated that the spliceosome can use a variety of 3' acceptor site sequences to pair with a given 5' donor site. The immunofluorescent visualization showed that the distribution of mutant STK11 was different from that of wild-type STK11, suggesting the mutation may be the causative effect on the dysfunction of the mutant protein. The rescue experiments indicated that the failure of suppressing mTOR phosphorylation by shRNA STK11 could be eliminated by supply of wild-type STK11 rather than mutant STK11.ConclusionWe identified a novel heterozygous mutation (c.921-2 A>C) in the STK11 in a Chinese PJS family. Haploinsufficiency of STK11 might contribute to the pathogenesis of the disease.
| S-EPMC8404226 | biostudies-literature
Project description:Peutz-Jeghers syndrome (PJS) is an autosomal dominantly inherited disease characterized by hamartomatous gastrointestinal polyps and mucocutaneous pigmentation, with an increased risk for various neoplasms, including gastrointestinal cancer. Recently, the PJS gene encoding the serine/threonine kinase STK11 (also named LKB1) was mapped to chromosome 19p13.3, and germline mutations were identified in PJS patients. We screened a total of ten Korean PJS patients (nine sporadic cases and one familial case including two patients) to investigate the germline mutations of the STK11 gene. By polymerase chain reaction-single-strand conformation polymorphism and DNA sequencing analysis, three kinds of mis-sense mutation and a frame-shift mutation were identified: codon 232 (TCC to CCC) in exon 5, codon 256 (GAA to GCA) in exon 6, codon 324 (CCG to CTG) in exon 8, and a guanine insertion at codon 342 resulting in a premature stop codon in exon 8. These mis-sense variants were not detected in 100 control DNA samples. Furthermore, we found an intronic mutation at the dinucleotide sequence of a splice-acceptor site: a one base substitution from AG to CG in intron 1, which may cause aberrant splicing. Most reported germline mutations of the STK11 gene in PJS patients were frame-shift or non-sense mutations resulting in truncated proteins. Together, these findings indicate that germline mis-sense mutations of the STK11 gene are found in PJS patients in addition to truncating mutations. The effects of these mutations on protein function require further examination. In summary, we found germline mutations of the STK11 gene in five out of ten Korean PJS patients.
| S-EPMC2363369 | biostudies-other