Screening for germ-line mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients

Abstract

We report here the result of a screening for germ-line mutations in the adenomatous polyposis coli (APC) gene in 61 new familial adenomatous polyposis (FAP) patients as well as a summary of the results of 150 patients. Examination of the entire coding region of the APC gene, based on a ribonuclease protection assay coupled with the polymerase chain reaction (PCR), disclosed mutations that were considered to cause significant defects in the APC product in 97 of 150 unrelated FAP patients. Our findings revealed the following characteristics of the germ-line mutations of APC: 1) the great majority of the mutations were found to truncate the APC product; 2) almost all of the mutations were located within the first half of the coding region; 3) no correlation was observed between the locations of germ-line mutations and extracolonic manifestations in FAP patients; 4) more than 80% of base substitutions in the APC gene were from cytosine to other nucleotides, nearly one-third of which occurred at the GpG site. Our results provide information helpful to an understanding of the APC gene and will also contribute to presymptomatic diagnosis of members in FAP families.

The APC gene product in normal and tumor cells.

“…Despite the inability to detect some mutant forms of the APC protein in FAP samples, a significant fraction of FAP mutations can be identified by direct analysis of the APC protein. From (5,6). This should allow simple presymptomatic diagnosis in a significant fraction of FAP kindreds.…”

“…Recently, a candidate tumor suppressor gene from chromosome 5q21, APC, was isolated and implicated in the development of FAP (1)(2)(3)(4). Further analyses of the APC gene in 150 kindreds indicate that APC mutations can account for most if not all cases of FAP (5,6). Carcinomas in FAP patients, however, account for <1% of all colorectal cancers.…”

AnEcoRI RFLP in humanAPC gene

“…Polymorphisms in the APC gene are very useful for examination of segregation of the mutated APC gene in the FAP kindreds, and also for studying the loss of heterozygosity at the APC region in certain tumors. Several polymorphisms in the APC gene were reported previously (Nagase et aL, 1992). Here we report a novel EcoRI-restriction fragment length polymorphism (RFLP) in the APC gene detected by Southern hybridization.…”

Genetic Susceptibility Factors in Aggressive Breast Cancer in African-American Women and the Effects of Carcinogens and Modifiers.

“…Approximately 95% of mutations occur in the 5' half of the gene, most of which result in protein truncation (Nagase et al 1992a;van der Luijt et al 1996). Patients who have frameshift mutations between codons 1250 and 1330 develop more than 5000 polyps, whereas mutations outside this region generally leads to less than 2000 polyps and milder disease (Nagase et al 1992b;Friedl et al 1996). Families with mutations located toward the 5' end of codon 158 are more likely to have heterogeneous features including delayed development of colonic polyposis ■ "*■ and colorectal cancer than families with more distal 5'mutations in the gene (Giardiello et al 1997).…”