BACKGROUND & AIMS: Hereditary nonpolyposis colorectal cancer (HNPCC) has been linked recently to a defect in repairing mismatched nucleotides in DNA. The aim of this study was to screen for germline mutations that result in prematurely truncated proteins in two of the mismatch repair genes identified at this time, hMLH1 and hMSH2, in a consecutive series of patients belonging to familial aggregations of colorectal cancer. METHODS: Nineteen individuals with colorectal cancer from 19 families were consecutively referred because of a strong positive family history of colorectal cancer. Premature truncation mutations in hMLH1 and hMSH2 were sought from lymphocyte RNA by using an in vitro transcription/translation (IVTT) assay. RESULTS: Protein truncating mutations in the hMLH1 or hMSH2 genes were found in 50% of families with HNPCC (6 of 12) but were not observed in any of the remaining familial aggregations that did not fulfill the standard criteria for HNPCC. In some of the IVTT-positive samples, the mutations were characterized by genomic sequencing. CONCLUSIONS: IVTT may be a practical method to accomplish primary screening of germline mutations in DNA mismatch pair genes in HNPCC; however, a broader approach is necessary to obtain a more complete picture of the mutational spectrum in HNPCC and other familial aggregations of colorectal cancer.
BACKGROUND & AIMS:Hereditary nonpolyposis colorectal cancer (HNPCC) has been linked recently to a defect in repairing mismatched nucleotides in DNA. The aim of this study was to screen for germline mutations that result in prematurely truncated proteins in two of the mismatch repair genes identified at this time, hMLH1 and hMSH2, in a consecutive series of patients belonging to familial aggregations of colorectal cancer. METHODS: Nineteen individuals with colorectal cancer from 19 families were consecutively referred because of a strong positive family history of colorectal cancer. Premature truncation mutations in hMLH1 and hMSH2 were sought from lymphocyte RNA by using an in vitro transcription/translation (IVTT) assay. RESULTS: Protein truncating mutations in the hMLH1 or hMSH2 genes were found in 50% of families with HNPCC (6 of 12) but were not observed in any of the remaining familial aggregations that did not fulfill the standard criteria for HNPCC. In some of the IVTT-positive samples, the mutations were characterized by genomic sequencing. CONCLUSIONS: IVTT may be a practical method to accomplish primary screening of germline mutations in DNA mismatch pair genes in HNPCC; however, a broader approach is necessary to obtain a more complete picture of the mutational spectrum in HNPCC and other familial aggregations of colorectal cancer.
Authors: Jerneja Tomsic; Sandya Liyanarachchi; Heather Hampel; Monika Morak; Brittany C Thomas; Victoria M Raymond; Anu Chittenden; Hans K Schackert; Stephen B Gruber; Sapna Syngal; Alessandra Viel; Elke Holinski-Feder; Stephen N Thibodeau; Albert de la Chapelle Journal: Int J Cancer Date: 2011-08-30 Impact factor: 7.396
Authors: G Marra; S D'Atri; C Corti; L Bonmassar; M S Cattaruzza; P Schweizer; K Heinimann; Z Bartosova; M Nyström-Lahti; J Jiricny Journal: Proc Natl Acad Sci U S A Date: 2001-06-19 Impact factor: 11.205
Authors: Sven Arnold; Daniel D Buchanan; Melissa Barker; Lesley Jaskowski; Michael D Walsh; Genevieve Birney; Michael O Woods; John L Hopper; Mark A Jenkins; Melissa A Brown; Sean V Tavtigian; David E Goldgar; Joanne P Young; Amanda B Spurdle Journal: Hum Mutat Date: 2009-05 Impact factor: 4.878