“Hot Spots” Can Burn You (2002)

Abstract Germline mutation in the APC gene predisposes to the rare familial adenomatous polyposis syndrome, in which hundreds to thousands of adenomatous polyps develop in the large intestine, as well as early-onset colorectal cancers. APC gene mutations are also found in approximately 80% of all sporadic colon cancers and appear to be the earliest mutations in the adenoma-carcinoma sequence (1) . Once the APC gene is lost through mutations in both copies or alleles and adenoma formation is complete, mutations in other colon cancer genes are necessary to continue the transformation to carcinoma. Recently, a polymorphism (variations of a gene that are found in >1% of the population) in the APC gene, I1307K, was found to confer a nearly 2-fold risk of colon cancer in individuals heterozygous for the allele (2) . The I1307K APC polymorphism is rarely found in the general population, but occurs in the Ashkenazi Jew population with carrier frequencies ranging from 5.9% to 7.3%. The I1307K polymorphism is a T-to-A transversion at nucleotide 3920. Laken et al. found that the I1307K allele is frequently mutated or lost in colonic tumors, suggesting that the nonmutated allele does not directly participate in the tumorigenic process, but may indirectly cause an unstable, hypermutable sequence or “hot spot” in an adjacent portion of the APC gene. This may lead to mutations and deletions at nearby sequences in the APC allele, which may account for the absence of the I1307k allele in cancers arising in carriers of the allele. Thus, this polymorphism may ultimately lead to inactivation of the APC allele through deletions on the same chromosome. Stern et al. sought to determine any predisposition to colonic adenoma formation associated with being heterozygous for eh I1307K APC polymorphism. To accomplish this, 3540 households in the Jewish community of Ottawa were sent invitations to participate as well as family questionnaires. Two hundred forty-two respondents with personal or family histories of colorectal cancer were selected, and nearly 80% underwent colonoscopy. All had blood drawn for detection of the I1307K allele of the APC gene using an allele-specific polymerase chain reaction assay, with two previously known heterozygotes for APC I1307K used as controls. The participants were divided into three subgroups: I) 22 participants (9%) having personal histories of colorectal cancer; II) 11 participants (5%) having personal histories of extracolonic cancer including melanoma (three), breast (four), skin (two), and bladder (two); and III) the remaining 209 participants with family histories but no personal histories of cancer. Results: The I1307K allele was found in 25/242 participants (10.3%). All were heterozygous for I1307K. Those with personal histories of any type of cancer (groups I and II) were 2–3 times as likely to carry the mutation as those with no cancer history (I = 27.3%, II = 18.2%, III = 8.1%). The difference between those with personal histories of colorectal cancer (group I) and those with no personal histories of cancer (group III) was statistically significant. No difference was seen regarding gender or number of first-degree relatives with colorectal cancer. Polyps were found in 44/189 participants (23%) who agreed to colonoscopy. There was no statistically significant difference in adenoma development between the groups. Group I had six patients decline colonoscopy, but in the 16 who underwent exams, only two lesions (solitary adenomas) were found, in two participants. Neither carried the I1307K allele, and none of the five I1307K carriers had polyps. Although 6% of gene carriers younger than 57 from all groups developed polyps, all were diminutive and hyperplastic. To evaluate the role of the APC I1307K allele in those with no personal histories of colorectal cancer groups II and III were combined. There was no difference between I1307K allele carriers and noncarriers with regard to all polyps found (23% in both groups), adenomas (11.8% and 12.8%), or hyperplastic polyps (6% and 8%). Importantly, 10/12 patients (83%) with multiple polyps and all four with tubovillous adenomas were noncarriers. Polyp size, number, location, histological subtype, and early development of adenomas were not correlated with carrier status.