title: Prevalence of MYH germline mutations in Swiss APC mutation-negative polyposis patients.
abstract: 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.
authors.affiliation: Research Group Human Genetics, Division of Medical Genetics, Center for Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Russell
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Judith
authors.initials: J
authors.lastname: Luz
authors.forename: Pierre
authors.initials: P
authors.lastname: Hutter
authors.forename: Pierre O
authors.initials: PO
authors.lastname: Chappuis
authors.forename: Claudine Rey
authors.initials: CR
authors.lastname: Berthod
authors.forename: Philippe
authors.initials: P
authors.lastname: Maillet
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Mueller
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D005260:Female; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D013557:Switzerland
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase