Identification of susceptibility genes for cancer in a genome-wide scan: results from the colon neoplasia sibling study.

TitleIdentification of susceptibility genes for cancer in a genome-wide scan: results from the colon neoplasia sibling study.
Publication TypeJournal Article
Year of Publication2008
AuthorsDaley, D, Lewis, S, Platzer, P, MacMillen, M, Willis, J, Elston, RC, Markowitz, SD, Wiesner, GL
JournalAm J Hum Genet
Volume82
Issue3
Pagination723-36
Date Published2008 Mar
ISSN1537-6605
KeywordsAdult, Aged, Breast Neoplasms, Chromosomes, Human, Pair 1, Colonic Neoplasms, Female, Genes, Neoplasm, Genetic Linkage, Genetic Predisposition to Disease, Genetic Testing, Genome, Human, Humans, Male, Middle Aged, Siblings
Abstract

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 (

DOI10.1016/j.ajhg.2008.01.007
Alternate JournalAm. J. Hum. Genet.
PubMed ID18313025
PubMed Central IDPMC2427227
Grant ListGM28356 / GM / NIGMS NIH HHS / United States
K23 1K23CA81308 / CA / NCI NIH HHS / United States
P30CA43703 / CA / NCI NIH HHS / United States
P41 RR0365 / RR / NCRR NIH HHS / United States
U01 CA82901 / CA / NCI NIH HHS / United States