Cicek, Mine S. and Cunningham, Julie M. and Fridley, Brooke L. and Serie, Daniel J. and Bamlet, William R. and Diergaarde, Brenda and Haile, Robert W. and Le Marchand, Loic and Krontiris, Theodore G. and Younghusband, H. Banfield and Gallinger, Steven and Newcomb, Polly A. and Hopper, John L. and Jenkins, Mark A. and Casey, Graham and Schumacher, Frederick and Chen, Zhu and DeRycke, Melissa S. and Templeton, Allyson S. and Winship, Ingrid and Green, Roger C. and Green, Jane S. and Macrae, Finlay A. and Parry, Susan and Young, Graeme P. and Young, Joanne P. and Buchanan, Daniel and Thomas, Duncan C. and Bishop, D. Timothy and Lindor, Noralane M. and Thibodeau, Stephen N. and Potter, John D. and Goode, Ellen L. (2012) Colorectal Cancer Linkage on Chromosomes 4q21, 8q13, 12q24, and 15q22. PLoS ONE, 7 (5). pp. 1-9. ISSN 1932-6203
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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.
|Keywords:||adult; article; cancer genetics; cancer registry; chromosome 12q; chromosome 12q24; chromosome 15q; chromosome 15q22; chromosome 4q; chromosome 4q21; chromosome 8q; chromosome 8q13; colorectal cancer; controlled study; dominant inheritance; family study; gene; genetic heterogeneity; genetic linkage; genome analysis; genotype; human; linkage analysis; major clinical study; microsatellite instability; mismatch repair; MMR gene; protein defect; protein expression; recessive inheritance; scoring system; single nucleotide polymorphism|
|Department(s):||Medicine, Faculty of|
|Date:||31 May 2012|
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