Molecular analysis of theAPCandMYHgenes in Czech families affected by FAP or multiple adenomas: 13 novel mutations

Abstract

Familial adenomatous polyposis (FAP) is an autosomal dominant predisposition to colorectal cancer and is caused by germline mutations in the adenomatous polyposis coli gene. The most prominent clinical manifestation is the presence of hundreds to thousands of colorectal polyps.A milder phenotype is found in patients affected with AFAP/ multiple adenomas. We screened the entire APC coding region using the combination of DGGE, PTT and direct sequencing and identified causative mutations in 52 of 77 patients. Thirteen of the mutations found were novel. In addition, we also tested 21 APC mutation/negative probands for the two most common mutations in the MYH gene. Four patients showed neither dominant transmission of the disease nor evidence of APC mutations. In one of them the most common biallelic germline mutation in the MYH gene was detected. Correlations between the localization of germline mutations and clinical manifestations of the diseases are discussed. © 2004 Wiley-Liss, Inc.KEY WORDS: adenomatous polyposis coli; APC; familial adenomatous polyposis; FAP; MYH; multiple adenomas INTRODUCTIONFamilial adenomatous polyposis (FAP, MIM# 175100) is a dominantly inherited colorectal cancer predisposition caused by germline mutations in the adenomatous polyposis coli gene ( APC, Gene Bank NM_000038.2). Its prevalence in the Czech Republic has been estimated to be 1 per 5000-7500. Clinically FAP is characterized by the development of hundreds to thousands of polyps, which are present mainly in the colon. The polyps appear during the teenage years and if left untreated they progress to colorectal cancer at the average age of 39 years. Because FAP shows nearly 100% penetration (Bisgaard et al., 1994) genetic testing of the at-risk relatives and the early prevention of cancer development are very important.The APC gene encodes a tumor suppressor protein expressed in a wide variety of tissues. In colonic epithelial 2 Vandrovcová et al.cells APC protein plays an essential role in the control of the cell cycle progression by preventing β-catenin accumulation. β-catenin activates transcription of specific target genes such as protooncogenes cyclin D1 and c-myc (Sieber et al., 2000). Germline mutations in the APC gene are found in about 80% of patients affected with FAP while inactivating somatic mutations occur in FAP tumors and i n most cases of sporadic colorectal carcinomas (Powell et al., 1992(Powell et al., , 1993Hutter et al., 2001). Germline mutations are scattered thorough the whole APC gene, however, they are predominantly distributed in the 5' half of the gene. About 95% of the mutations are nonsense or truncating frameshift mutations. Mutational analysis has revealed that there is an apparent correlation between the mutation site and the phenotype of patients. This concordance has been proved especially for the severity of the disease and some extracolonic manifestations, such as desmoid tumors and congenital hypertrophy of the retinal pigment epithelium (CHRPE) (Fearnhead et al., 2001). In addition to the class...

APC mutation spectrum of Norwegian familial adenomatous polyposis families: high ratio of novel mutations

“…Whether identical at genome level, remains to be seen. The frequent Wve base pair deletions at codons 1,061 and 1,309 detected in 5 (7.3%) and eight families (11.6%), respectively, is in accordance with other reports (Miyoshi et al 1992;Vandrovcova et al 2004), although signiWcantly higher and lower proportions have been reported (Nagase and Nakamura 1993;De Rosa et al 2004;García-Lozano et al 2005). Since the frequent 5 bp deletions of 1061 and 1309 are straightforwardly detected irrespective of methods being applied, the ratio between these two should represent solid indicators of ethnic variations in mutation spectra.…”

Germline MYH mutations in a clinic‐based series of Canadian multiple colorectal adenoma patients

“…While some groups have conducted whole MYH gene mutation screening in multiple adenoma patients to identify uncommon, but otherwise important pathogenic MYH mutations [9,[11][12][13][20][21][22], some published series have restricted mutation testing to only include the Y165C and G382D mutations [19,23]. Heterozygous Y165C and G382D mutation carriers may be at slightly increased risk of developing colorectal adenomas and cancer, however, a definitive estimate of this risk has not been determined with certainty [9,12,13,19,[24][25][26].…”

A novel functionally deficientMYH variant in individuals with colorectal adenomatous polyposis

“…Some of the APC negative FAP or AFAP cases have recently been found to be attributable to MAP (De Rosa, et al, 2004;Gismondi, et al, 2004;Vandrovcova, et al, 2004;Venesio, et al, 2004;Wang, et al, 2004). Patients with biallelic MYH mutations seem to have a phenotype partially overlapping with FAP, although MAP patients tend to have fewer adenomas and more advanced age at disease onset (Jones, et al, 2002;.…”