Novel germline mutation (300-305delAGTTGA) in the human MSH2 gene in hereditary non-polyposis colorectal cancer (HNPCC) (original) (raw)
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Seven novel MLH1 and MSH2 germline mutations in hereditary nonpolyposis colorectal cancer
Human …, 2002
(MMR) genes. The majority of mutations occur in MLH1 and MSH2. We report hereby seven novel germline mutations in these two genes (five in MLH1 and two in MSH2). All mutations have been found in families fulfilling criteria of the Bethesda guidelines and four of which also fulfilled the Amsterdam criteria. We identified three insertions or deletions of 1 bp leading to premature stop codons (MLH1: c.341delC, c.1413-1414insA; MSH2: c.1119delG) and three nonsense mutations (MLH1: c.67G>T [E23X], c.436C>T [Q146X]; MSH2 : c.1857T>G [Y619X]). The corresponding tumors showed a high level of microsatellite instability (MSI-H) and a complete loss of expression of the affected protein. In addition, a missense mutation in MLH1 was identified (c.1984A>C [T662P]). The respective tumor also showed a high level of microsatellite instability but a reduced, rather then lost, expression of the MLH1-protein. This missense mutation was not found in 107 healthy control individuals and in 54 HNPCC patients.
Familial Cancer, 2005
This study searched for mutations in the MLH1 and MSH2 genes in 23 unrelated Colombian families with suspected hereditary nonpolyposis colorectal cancer (HNPCC). The families were grouped according to the fulfillment of the Amsterdam II criteria or the Bethesda guidelines. We screened all probands by single-strand conformational polymorphism (SSCP) and direct DNA sequencing. Eleven families fulfilled the Amsterdam criteria II and 12 families the Bethesda guidelines. Germline mutations were detected in 11 families, which corresponds to a mutation detection rate of 48%. When only families fulfilling the Amsterdam II criteria were analyzed, the mutation detection rate rose to 82%. Only 8% of the mutation detection rate was found in families following the Bethesda guidelines. Three mutations were shared by two different families, which corresponds to a total of eight different mutations, seven of them found in the MLH1 gene and one in the MSH2 gene. We have identified four mutations that have not been previously reported to the International Collaborative Group of HNPCC. Three of these are pathogenic, a single base substitution (C > T) at codon 640, exon 17, a G deletion at codon 619, exon 16 and in the MLH1 gene and a two-nucleotide deletion (TG) at codon 184, exon 3 in the MSH2. Also, an unclassified variant, a substitution (C > G) at the codon 141, exon 5 of the MLH1, was detected.
Wiener klinische Wochenschrift, 2005
Germ-line mutations in mismatch repair genes are associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, which is characterized by susceptibility to cancer of the colon, endometrium, small bowel or urothelium at an unusually young age and with a high degree of penetration in all generations. One hundred and nine individuals from 46 Austrian families who fulfilled the Amsterdam criteria (n = 29) or at least one of the Bethesda guidelines (n = 17) were analyzed for mutations in MLH1 and MSH2. Microsatellite instability was determined in the tumors of index persons and affected relatives. High-grade instability was present in 60.6% of the tumor samples from index patients. Twenty-three germ-line DNA sequence variants in 24/46 families and four somatic mutations in three tumors were detected in MLH1 and MSH2. Fifteen mutations are novel. None of the newly identified germ-line variants was found in 100 alleles of healthy control individuals. We were able to charac...
JAMA, 2004
Context Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is caused by mutations in the mismatch repair genes and confers an extraordinarily high risk of colorectal, endometrial, and other cancers. However, while carriers of these mutations should be identified, counseled, and offered clinical surveillance, at present the mutations are not tested for in mutation analyses. Objective To describe the prevalence of a large genomic deletion encompassing exons 1 to 6 of the MSH2 gene that is widespread in the US population as a result of a founder effect. Design, Setting, and Patients Ongoing genealogical and historical study conducted to assess the origin and spread of an MSH2 mutation previously identified in 9 apparently unrelated families with putative HNPCC and living in widely different geographic locations in the United States.
Gastroenterology, 2020
BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with
Familial Cancer, 2009
Microsatellite instability (MSI) is present in more than 90% of colorectal cancers of patients with Lynch syndrome, and is therefore a feasible marker for the disease. Mutations in MLH1, MSH2, MSH6 and PMS2, which are one of the main causes of deficient mismatch repair and subsequent MSI, have been linked to the disease. In order to establish the role of each of the 4 genes in Slovenian Lynch syndrome patients, we performed MSI analysis on 593 unselected CRC patients and subsequently searched for the presence of point mutations, larger genomic rearrangements and MLH1 promoter hypermethylation in patients with MSI-high tumours. We detected 43 (7.3%) patients with MSI-H tumours, of which 7 patients (1.3%) harboured germline defects: 2 in MLH1, 4 in MSH2, 1 in PMS2 and none in MSH6. Twenty-nine germline sequence variations of unknown significance and 17 deleterious somatic mutations were found. MLH1 promoter methylation was detected in 56% of patients without detected germline defects and in 1 (14%) suspected Lynch syndrome. Due to the minor role of germline MSH6 mutations, we adapted the Lynch syndrome detection strategy for the Slovenian population of CRC patients, whereby germline alterations should be first sought in MLH1 and MSH2 followed by a search for larger genomic rearrangements in these two genes. When no germline mutations are found tumors should be further tested for the presence of germline defects in PMS2 and MSH6. The choice about which gene should be tested first can be guided more accurately by the immunohistochemical analysis. Our study demonstrates that the incidence of MMR mutations in a population should be known prior to the application of one of several suggested strategies for detection of Lynch syndrome.
Journal of Sciences, …, 2009
Hereditary nonpolyposis colorectal cancer is the most common form of hereditary colorectal cancers accounting for 5 to 10% of all colon carcinoma. It is inherited in an autosomal dominant mode and caused by hereditary mutations in mismatch repair genes (MMR) chiefly MLH1 and MSH2. The lifetime risk of colon cancer in affected persons is 80%. Screening, prevention strategies and consequently treatment options will be improved by understanding of the genetic basis of this disorder. The aim of this study was to assess mutations in MLH1 and MSH2 genes in a subset of Iranian HNPCC patients. The families that fulfill Amsterdam criteria were selected as HNPCC families. Genomic DNA was extracted from the peripheral blood of the samples and mutations of MLH1 and MSH2 were detected by PCR-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing techniques. Hereditary mutations were found in 20 cases. Of these mutations, 14 were found in MLH1 and 6 in MSH2 genes thus MLH1 gene had higher mutation rate than MSH2. Eighteen out of 20 detected mutations in our population were previously reported and two were novel. Our results demonstrated that mutation range as well as genes involved in HNPCC is different from one region to other and characterizing mutations could be very helpful in diagnosis of the at risk individuals.
Germ-line msh6 mutations in colorectal cancer families
Cancer research, 1999
Hereditary nonpolyposis colorectal carcinoma (HNPCC) is due primarily to inherited mutations in two mismatch repair genes, MSH2 and MLH1, whereas germ-line mutations in other mismatch repair genes are rare. We examined the frequency of germ-line msh6 mutations in a population-based series of 140 colorectal cancer patients, including 45 sporadic cases, 91 familial non-HNPCC cases, and 4 HNPCC cases. Among the 91 population-based familial non-HNPCC cases, germ-line msh6 mutations were found in 6 patients (7.1% of probands analyzed; median age at diagnosis, 61 years). These mutations included a splice site mutation, a frameshift mutation, two missense mutations that were demonstrated to be loss of function mutations, and two missense mutations for which functional studies were not possible. In contrast, germ-line msh6 mutations were not found in any of the 45 sporadic cases and the 4 HNPCC cases in the population-based series or in the second series of 58 clinic-based, primarily HNPCC ...
Cancer Research, 2009
An accurate algorithm is essential for effective molecular diagnosis of hereditary colorectal cancer (CRC). Here, we have extended the analysis of 71 CRC cases suspected to be Lynch syndrome cases for MSH2, MLH1, MSH6, and PMS2 gene defects. All cases were screened for mutations in MSH2, MLH1, and MSH6, and all cases where tumors were available were screened for microsatellite instability (MSI) and expression of MSH2 and MLH1. Subsequently, mutation-negative cases were screened for MLH1 methylation and mutations in PMS2. Of the MSI-high (MSI-H) cases, 96% had a mismatch repair (MMR) gene defect, mostly involving MSH2 or MLH1; one PMS2 mutation, one MLH1 epimutation, and no MSH6 mutations were found. Four of the 28 MSI-H cases, including one Amsterdam criteria case, had biallelic tumor MLH1 methylation, indicating that sporadic cases can be admixed in with Lynch syndrome cases, even those meeting the strongest criteria for Lynch syndrome. MMR gene defects were found in similar freque...