GENETIC TESTING Volume 11, Number 3, 2007 © Mary Ann Liebert, Inc. DOI: 10.1089/gte.2007.9995 Similar Colorectal Cancer Risk in Patients with Monoallelic and Biallelic Mutations in the MYH Gene Identified in a Population with Adenomatous Polyposis SYLVIANE OLSCHWANG, 1 HÉLÈNE BLANCHÉ, 2 CÉLINE DE MONCUIT, 3 and GILLES THOMAS 4 ABSTRACT A large proportion of non-FAP non-HNPCC patients with multiple colorectal adenomas have been reported to carry germline mutations on the MYH gene. Although the number of adenomas appears to be dependent on the number of mutated MYH alleles present in a patient, little is known on the relation of this number with cancer risk. Four hundred fifty-three APC-negative patients with more than five colorectal adenomas were screened for mutations on the entire coding sequence of the MYH gene. Pathogenic mutations were ini- tially found in 74 patients without extradigestive tumors (22.5%) and subsequently in 75 at-risk relatives. Polyposis was more severe in cases with biallelic mutations. However, mutation copy number was correlated neither with the age at diagnosis of adenomas or adenocarcinomas, nor with the presence of a family history of colorectal tumors. Heterozygous and homozygous MYH mutation carriers were both at high risk for syn- chronous cancers (24% in colorectum and 16% in the upper gastrointestinal tract), but did not demonstrate an increased risk for extradigestive tumors. MYH-associated polyposis is a frequent inherited colorectal can- cer predisposition with a strong dominance component. From age 25–30, MYH mutation carriers should be proposed an early screening program, which includes endoscopies of the upper digestive tract and the col- orectum every 2 years. 315 INTRODUCTION F AMILIAL ADENOMATOUS POLYPOSIS (FAP) is a well-de- scribed, autosomal dominant inherited syndrome with near complete penetrance (Galiatsatos and Foulkes 2006) associated with APC mutation. Although the phenotypic hallmark of FAP has traditionally been described as the presence of more than 100 colorectal adenomas, a subset of APC gene carriers pre- sents with fewer colorectal adenomas. Compared with classic FAP, these patients have a later age of onset of both adenomas and colorectal adenocarcinomas, a more proximal colonic dis- tribution and, with the exception of desmoid tumors, lack extr- adigestive manifestation (Hernegger et al. 2002). This variant disease has been initially referred to as “attenuated adenoma- tous polyposis coli” (AAPC) (Spirio et al. 1993) and more re- cently included in a clinical entity called “attenuated familial adenomatous polyposis” (AFAP). Genotype–phenotype studies have shown that the most frequently encountered APC muta- tions in AAPC cases are located in the 5 end of the gene. Mu- tations in exon 9A lead to a similar phenotype, whereas patients with mutations in the 3 part of the APC gene exhibit desmoid tumors in addition to attenuated colorectal polyposis (Knudsen et al. 2003). A second gene, MYH, was recently found associated to the attenuated phenotype (Al-Tassan et al. 2002; Jones et al. 2002). In contrast to the major known colorectal cancer predisposi- tions that demonstrate an autosomal dominant pattern of inher- itance, MYH mutations, which were initially observed in ho- mozygous or compound heterozygous carriers, were described as being responsible for a recessive syndrome, termed MYH- 1 Inserm, U599, Centre de Recherches en Cancérologie de Marseille, Molecular Oncology, Marseille, F-13009 France; Institut Paoli-Calmettes, Marseille, F-13009 France; Université de la Méditerranée, F-13007, Marseille, France. 2 Fondation Jean Dausset, Paris, France. 3 Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France. 4 Division of Cancer, Epidemiology and Genetics, NCI/NIH, Gaithersburg, Maryland.