Colorectal Cancer Linkage on Chromosomes 4q21, 8q13, 12q24, and 15q22

Mine Cicek, Julie Cunningham, Brooke Fridley, Daniel Serie, William Bamlet, Brenda Diergaarde, Robert Haile, Loic Le Marchand, Theodore Krontiris, H Banfield Younghusband, Steven Gallinger, Polly Newcomb, John Hopper, Mark Jenkins, Graham Casey, Frederick Schumacher, Zhu Chen, Melissa DeRycke, Allyson Templeton, Ingrid WinshipRoger Green, Jane Green, F Macrae, Susan Parry, Graeme Young, Joanne Young, Daniel Buchanan, Duncan Thomas, D Bishop, N Lindor, S Thibodeau, J Potter, Ellen Goode

    Research output: Contribution to journalArticle

    20 Citations (Scopus)

    Abstract

    A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated.

    Original languageEnglish
    Article numbere38175
    Pages (from-to)e38175
    Number of pages9
    JournalPLoS One
    Volume7
    Issue number5
    DOIs
    Publication statusPublished - 31 May 2012

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