Title: Germline mutations of MLH3 in Korean hereditary nonpolyposis colorectal cancer
Abstract: 1324 The autosomal dominantly inherited form of colorectal polyposis and cancer, familial adenomatous polyposis (FAP), is in the large majority of cases caused by germline mutations in the APC gene (5q21-q22). The APC tumour suppressor also has a role in sporadic colorectal tumorigenesis. Mutational screening of the APC gene was carried out on family members of the Swedish polyposis registry with the aim to detect the pathogenic mutations to enable presymptomatic diagnosis and identification of genotype-phenotype correlations. The APC gene (encoding 2843 aminoacids) consists of 15 exons where exon 15 has a size of more than six kilobases. We used an initial RNA and DNA based protein truncation test (PTT) and subsequential sequencing of the PTT-fragments to detect a majority of the disease-causing mutations, which mainly are protein truncating. When no chain terminating mutation was found, exon-specific techniques as well as multiplex ligation-dependent probe amplification (MLPA) were used to search for the presence of in-frame mutation or large deletion/duplication respectively. Seventy-two pathogenic mutations were found in 114 families. The mutation detection rate in families with classic FAP was 75% (69/92). Of the identified mutations, 40 were small (one to five bp) deletion/insertion mutations, 22 were nonsense mutations, four were mutations affecting splice sites, and six were gross deletions, among them four deletions of one or more exons. Thirty-eight of the detected mutations, including gross deletions and introductions of cryptic splice sites, were novel. One of the patients displaying an attenuated form of FAP (AFAP) was a rare case of mosaicism. Another AFAP patient carried a novel nonsense mutation in the first exon of the APC gene. The identified causes of disease in these two AFAP patients are in agreement with the notion that the mild phenotype can arise either as a result of mutations in the first five exons of the APC gene, or as a result of lower expression of the mutated allele. However, a third AFAP patient was shown to carry a mutation causing a premature stop codon in the beginning of exon 15. Six missense mutations were also identified in the material. The APC E1317Q variant, previously reported not to be present among Swedish colorectal cancer patients was identified in three unrelated families.
Publication Year: 2004
Publication Date: 2004-04-01
Language: en
Type: article
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