The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history

Abstract

Classical familial adenomatous polyposis (FAP) is a high-penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene. A variant of FAP is attenuated adenomatous polyposis coli, which results from germ-line mutations in the 5' and 3' regions of the APC gene. Attenuated adenomatous polyposis coli patients have "multiple" colorectal adenomas (typically fewer than 100) without the florid phenotype of classical FAP. Another group of patients with multiple adenomas has no mutations in the APC gene, and their phenotype probably results from variation at a locus, or loci, elsewhere in the genome. Recently, however, a missense variant of APC (I1307K) was described that confers an increased risk of colorectal tumors, including multiple adenomas, in Ashkenazim. We have studied a set of 164 patients with multiple colorectal adenomas and/or carcinoma and analyzed codons 1263-1377 (exon 15G) of the APC gene for germ-line variants. Three patients with the I1307K allele were detected, each of Ashkenazi descent. Four patients had a germ-line E1317Q missense variant of APC that was not present in controls; one of these individuals had an unusually large number of metaplastic polyps of the colorectum. There is increasing evidence that there exist germ-line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma, but without the florid phenotype of classical FAP, and possibly with importance for colorectal cancer risk in the general population.

Figure 1

ARMS PCR analysis for APC I1307K. Agarose gel electrophoresis of ARMS PCR products. The upper row (← I) shows I1307-specific (wild-type) PCR products, and the lower row (K →) shows K1307-specific products at 255 bp. In any given numbered lane the products in the two rows are from the same individual; lanes labeled “M” are 100-bp ladder DNA marker. Lanes 1–4, 6, and 7 are from I1307K-negative individuals; lanes 5 and 8 are from I1307K-carrying patients 2–33 and 2–49, respectively; lane 9 is an I1307K-positive control; lanes 10 and 11 are from E1317Q-carrying patients 2–80 and 2–82, respectively; and lane 12 is a known homozygous, wild-type negative control.

Figure 2

Pedigree of APC I1307K-carrying individual 1–14. Symbols: solid, individuals affected with gastrointestinal cancers; half-solid, other cancers (not smoking related); quarter-solid, smoking-related cancers; central dot, colorectal adenoma(s); N, no tumors found at colonoscopy. Generations are given on the left in roman numerals. Beneath the symbols are given individual numbers, by generations. Below the individual numbers are given the known tumor type(s) (carcinomas unless otherwise specified) or other cause of death affecting that individual and the age at diagnosis, when known (including any colonoscopy results; nil, no tumors found). Shown below the diagnoses, in parentheses, is the age at death. The proband (individual IV.5; patient 1–14) is indicated with an arrow and is a heterozygous carrier of APC I1307K. Individuals IV.4 and IV.5 have had one surveillance colonoscopy, while IV.2 has had three, commencing at age 48 years; other individuals in generation IV whose phenotypes are unknown have been omitted for clarity. II.7 and II.8 were first cousins through I.2.