期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 82, 期 3, 页码 723-736出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2008.01.007
关键词
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资金
- NCI NIH HHS [U01 CA082901, K23 CA081308, P30CA43703, K23 1K23CA81308, P30 CA043703, U01 CA82901] Funding Source: Medline
- NCRR NIH HHS [P41 RR0365] Funding Source: Medline
- NIGMS NIH HHS [GM28356, R37 GM028356, R01 GM028356] Funding Source: Medline
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Americans and is the second leading cause of cancer mortality. Only a minority (similar to 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 lp3l.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 (<= 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 demonstrated that using clinical information, unaffected siblings, and family history can increase the analytical power of a linkage study.
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