STUDIES IN COLORECTAL AND RELATED CANCERS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Americans and is the second leading cause of cancer mortality. Only a minority ( approximately 5%) of familial CRC can be explained by known genetic variants. To identify susceptibility genes for familial colorectal neoplasia, the colon neoplasia sibling study conducted a comprehensive, genome-wide linkage scan of 194 kindreds. Clinical information (histopathology, size and number of polyps, and other primary cancers) was used in conjunction with age at onset and family history for classification of the families into five phenotypic subgroups (severe histopathology, oligopolyposis, young, colon/breast, and multiple cancer) prior to analysis. By expanding the traditional affected-sib-pair design to include unaffected and discordant sib pairs, analytical power and robustness to type I error were increased. Sib-pair linkage statistics and Haseman-Elston regression identified 19 linkage peaks, with interesting results for chromosomes 1p31.1, 15q14-q22, 17p13.3, and 21. At marker D1S1665 (1p31.1), there was strong evidence for linkage in the multiple-cancer subgroup (p = 0.00007). For chromosome 15q14-q22, a linkage peak was identified in the full-sample (p = 0.018), oligopolyposis (p = 0.003), and young (p = 0.0009) phenotypes. This region includes the HMPS/CRAC1 locus associated with hereditary mixed polyposis syndrome (HMPS) in families of Ashkenazi descent. We provide compelling evidence linking this region in families of European descent with oligopolyposis and/or young age at onset (<or=51) phenotypes. We found linkage to BRCA2 in the colon/breast phenotypic subgroup and identified a second locus in the region of D21S1437 segregating with, but distinct from, BRCA2. Linkage to 17p13.3 at marker D17S1308 in the breast/colon subgroup identified HIC1 as a candidate gene. We previously identified in the severe histopathology subgroup the chromosomal region 9q22.2-31.2 as harboring a susceptibility locus for colorectal neoplasia. We conclude that there remains an unidentified susceptibility locus in the region. Further study of this region definitely excludes the possibility of the TGFBR1*6A allele increasing the risk of colorectal neoplasia in our sample population. A recent study validating linkage of colorectal cancer to chromosome 9q also excluded the TGFBR1*6A allele as a disease-causing variant in that sample. In view of the familial aggregation of colon and breast cancer, we performed a meta-analysis of variants that may underly susceptibility to breast cancer. The N-acetyltransferase 2 gene (NAT2) product is an enzyme important in carcinogen metabolism via activation and detoxification pathways. We extracted all relevant data to examine evidence for a main effect (i.e., the effect in a model that does not include any interactions) of NAT2 phenotype and genotype on breast cancer risk. We summarized the evidence for modification by smoking and meat intake, sources of exposure to aromatic and heterocyclic amines, respectively, which are metabolized by NAT2. We identified seven studies that measured NAT2 phenotype and 20 studies that deduced phenotype via genotyping. We found no evidence for heterogeneity (Cochran's Q statistic p=0.74) and no statistically significant increased risk from NAT2 acetylation (slow/rapid) for breast cancer (summary odds ratio=1.02, 95% confidence interval: 0.95, 1.08). These results suggest that there is no overall association between the NAT2 slow- or rapid-acetylation phenotype and breast cancer risk. However, some evidence suggests that smoking may modify this association.