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Prevalence of MYH germline mutations in Swiss APC mutation‐negative polyposis patients
Author(s) -
Russell Anna M.,
Zhang Jian,
Luz Judith,
Hutter Pierre,
Chappuis Pierre O.,
Berthod Claudine Rey,
Maillet Philippe,
Mueller Hansjakob,
Heinimann Karl
Publication year - 2005
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21470
Subject(s) - mutyh , germline mutation , adenomatous polyposis coli , mutation , familial adenomatous polyposis , cancer research , germline , medicine , genetics , biology , colorectal cancer , cancer , gene
In 10–30% of patients with classical familial adenomatous polyposis (FAP) and up to 90% of those with attenuated (<100 colorectal adenomas; AFAP) polyposis, no pathogenic germline mutation in the adenomatous polyposis coli ( APC ) gene can be identified ( APC mutation‐negative). Recently, biallelic mutations in the base excision repair gene MYH have been shown to predispose to a multiple adenoma and carcinoma phenotype. This study aimed to ( i ) assess the MYH mutation carrier frequency among Swiss APC mutation‐negative patients and ( ii ) identify phenotypic differences between MYH mutation carriers and APC/MYH mutation‐negative polyposis patients. Seventy‐nine unrelated APC mutation‐negative Swiss patients with either classical ( n = 18) or attenuated ( n = 61) polyposis were screened for germline mutations in MYH by dHPLC and direct genomic DNA sequencing. Overall, 7 (8.9%) biallelic and 9 (11.4%) monoallelic MYH germline mutation carriers were identified. Among patients with a family history compatible with autosomal recessive inheritance ( n = 45), 1 (10.0%) out of 10 classical polyposis and 6 (17.1%) out of 35 attenuated polyposis patients carried biallelic MYH alterations, 2 of which represent novel gene variants (p.R171Q and p.R231H). Colorectal cancer was significantly ( p < 0.007) more frequent in biallelic mutation carriers (71.4%) compared with that of monoallelic and MYH mutation‐negative polyposis patients (0 and 13.8%, respectively). On the basis of our findings and earlier reports, MYH mutation screening should be considered if all of the following criteria are fulfilled: ( i ) presence of classical or attenuated polyposis coli, ( ii ) absence of a pathogenic APC mutation, and ( iii ) a family history compatible with an autosomal recessive mode of inheritance. © 2005 Wiley‐Liss, Inc.