Background & Aims:MYH-associated polyposis is a recently described disease that is characterized by multiple colorectal adenomas and a recessive pattern of inheritance. Individuals with MYH-associated polyposis ha...Background & Aims:MYH-associated polyposis is a recently described disease that is characterized by multiple colorectal adenomas and a recessive pattern of inheritance. Individuals with MYH-associated polyposis have biallelic mutations in MYH, a base excision repair gene, and are negative for germline mutations in the APC gene. In this study, the 2 most prevalent MYH mutations in white persons, Y165C and G382D, were analyzed for their presence in 984 subjects selected from 3 groups: 400 undergoing screening colonoscopy and found to have 0-3 polyps, 444 with colorectal cancer (CRC), and 140 referred for APC mutation analysis in which a germline mutation was not identified. Methods: Genotyping for Y165C and G382D was performed by Pyrosequencing. Results: Biallelic mutations for Y165C and/or G382D were not found in any of those undergoing screening colonoscopy with 0-3 polyps (n =400), in those APC-negative patients with < 20 adenomatous polyps (n = 26), or in those with CRC who were older than 50 years (n = 328). Furthermore, these 2 MYH mutations were not found among patients whose tumors showed the presence of defective DNA mismatch repair (n = 62). However, the presence of biallelic germline MYH mutations correlated with the presence of ≥ 20 adenomatous polyps. Interestingly, 2 of the 116 individuals with CRC diagnosed at 50 years of age or younger also presented with biallelic germline mutations in MYH. Conclusions: These data suggest that screening of MYH should be considered not only in patients with multiple polyps but also in patients with early-onset CRC.展开更多
Background & Aims: A significant proportion of Lynch syndrome cases are believed to be due to large genomic alterations in the mismatch repair genes hMLH1 and hMSH2. However, previous studies have not adequately i...Background & Aims: A significant proportion of Lynch syndrome cases are believed to be due to large genomic alterations in the mismatch repair genes hMLH1 and hMSH2. However, previous studies have not adequately identified the frequency and scope of such mutations, and routine clinical Lynch syndrome testing often does not include analysis for these mutations. Our aim was to characterize hMLH1 and hMSH2 genomic rearrangements in a large population of suspected Lynch syndrome patients. Methods: A total of 365 samples from probands referred for genetic testing for Lynch syndrome were analyzed for the presence of large genomic alterations in hMLH1 or hMSH2 by using a combination of techniques. Samples with a deletion in exons 1- 6 in hMSH2 were further characterized by polymerase chain reaction to establish the presence of the hMSH2 American founder deletion. Results: An hMLH1 or hMSH2 mutation was identified in 153 cases, and, of these, 12 of 67 (17.9% ) and 39 of 86 (45.3% ) had a large genomic alteration in hMLH1 and hMSH2, respectively. Overall, 6 different hMLH1 and 12 different hMSH2 deletions/ duplications, including 10 novel mutations, were identified. Analysis of the hMSH2 exon 1- 6 deletion samples showed that 13 of 18 (72.2% ) had the American founder deletion. Conclusions: These data show a high frequency and diverse spectrum of large genomic alterations in hMLH1 and hMSH2 in suspected Lynch syndrome patients. Thus, a comprehensive mutation identification strategy that includes the ability to detect large genomic rearrangements is imperative for the clinical genetic identification of Lynch syndrome patients and families.展开更多
文摘Background & Aims:MYH-associated polyposis is a recently described disease that is characterized by multiple colorectal adenomas and a recessive pattern of inheritance. Individuals with MYH-associated polyposis have biallelic mutations in MYH, a base excision repair gene, and are negative for germline mutations in the APC gene. In this study, the 2 most prevalent MYH mutations in white persons, Y165C and G382D, were analyzed for their presence in 984 subjects selected from 3 groups: 400 undergoing screening colonoscopy and found to have 0-3 polyps, 444 with colorectal cancer (CRC), and 140 referred for APC mutation analysis in which a germline mutation was not identified. Methods: Genotyping for Y165C and G382D was performed by Pyrosequencing. Results: Biallelic mutations for Y165C and/or G382D were not found in any of those undergoing screening colonoscopy with 0-3 polyps (n =400), in those APC-negative patients with < 20 adenomatous polyps (n = 26), or in those with CRC who were older than 50 years (n = 328). Furthermore, these 2 MYH mutations were not found among patients whose tumors showed the presence of defective DNA mismatch repair (n = 62). However, the presence of biallelic germline MYH mutations correlated with the presence of ≥ 20 adenomatous polyps. Interestingly, 2 of the 116 individuals with CRC diagnosed at 50 years of age or younger also presented with biallelic germline mutations in MYH. Conclusions: These data suggest that screening of MYH should be considered not only in patients with multiple polyps but also in patients with early-onset CRC.
文摘Background & Aims: A significant proportion of Lynch syndrome cases are believed to be due to large genomic alterations in the mismatch repair genes hMLH1 and hMSH2. However, previous studies have not adequately identified the frequency and scope of such mutations, and routine clinical Lynch syndrome testing often does not include analysis for these mutations. Our aim was to characterize hMLH1 and hMSH2 genomic rearrangements in a large population of suspected Lynch syndrome patients. Methods: A total of 365 samples from probands referred for genetic testing for Lynch syndrome were analyzed for the presence of large genomic alterations in hMLH1 or hMSH2 by using a combination of techniques. Samples with a deletion in exons 1- 6 in hMSH2 were further characterized by polymerase chain reaction to establish the presence of the hMSH2 American founder deletion. Results: An hMLH1 or hMSH2 mutation was identified in 153 cases, and, of these, 12 of 67 (17.9% ) and 39 of 86 (45.3% ) had a large genomic alteration in hMLH1 and hMSH2, respectively. Overall, 6 different hMLH1 and 12 different hMSH2 deletions/ duplications, including 10 novel mutations, were identified. Analysis of the hMSH2 exon 1- 6 deletion samples showed that 13 of 18 (72.2% ) had the American founder deletion. Conclusions: These data show a high frequency and diverse spectrum of large genomic alterations in hMLH1 and hMSH2 in suspected Lynch syndrome patients. Thus, a comprehensive mutation identification strategy that includes the ability to detect large genomic rearrangements is imperative for the clinical genetic identification of Lynch syndrome patients and families.
