A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22.2-31.2

Abstract

Colorectal cancer is the second most leading cause of cancer death among adult Americans. Two autosomal dominant hereditary forms of the disease, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, together account for perhaps 5% of all cases. However, in approximately 20% of additional colon cancer cases, the affected individuals report a family history of colon cancer in a first-degree relative. Similar familial clusters of colon cancer and early-onset colon adenomas have also been reported. To determine whether such familial aggregations arise by chance or reflect a hereditary colon cancer susceptibility, we conducted a whole genome scan to test for genetic linkage in 53 kindreds in which two or more siblings were affected by age 65 or younger with colon cancer or with advanced colon adenomas that were >1 cm in size or that showed high-grade dysplasia. In this cohort we found genetic linkage of disease (P = 0.00045) to chromosomal region 9q22.2-31.2 in a pattern consistent with autosomal dominant disease alleles. These data suggest that a single locus can contribute to disease susceptibility in a subset of patients with nonsyndromic forms of familial colorectal neoplasia.

Fig. 1.

Comparisons of P values for linkage among concordantly and discordantly affected sibling pairs. Shown on the x axis are the P values for linkage among 74 concordantly affected sibling pairs for the six chromosomal regions listed in Table 1 that show the most extreme allele sharing among concordant sibling pairs. Shown on the y axis are the P values for linkage at these same six chromosomal regions as determined by analysis of the degree of deficient allele sharing among 94 discordant sibling pairs. Red diamond designates the chromosome 9 linkage region marked by D9S1786. Other chromosomal locations are indicated in parentheses, with two loci noted that map to chromosome 6.

Fig. 2.

Linkage of the D9S1786 region of chromosome 9 to development of familial colorectal neoplasia. Chromosome 9, in cM, is depicted along the x axis. Distances of the markers were calculated relative to the first typed marker on the chromosome, D9S2169. The y axis plots pP = (-log₁₀[P value for linkage]). Red symbols depict pP values for linkage as determined by the mean test among concordantly affected sibling pairs. Blue symbols depict pP values for linkage as determined by the Haseman–Elston method employing all affected and unaffected siblings. pP values have not been corrected for multiple hypothesis testing; a pP value of 4 corresponds to a corrected logarithm of odds score of 3.