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Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22
Authors:Cicek Mine S  Cunningham Julie M  Fridley Brooke L  Serie Daniel J  Bamlet William R  Diergaarde Brenda  Haile Robert W  Le Marchand Loic  Krontiris Theodore G  Younghusband H Banfield  Gallinger Steven  Newcomb Polly A  Hopper John L  Jenkins Mark A  Casey Graham  Schumacher Fredrick  Chen Zhu  DeRycke Melissa S  Templeton Allyson S  Winship Ingrid  Green Roger C  Green Jane S  Macrae Finlay A  Parry Susan  Young Graeme P  Young Joanne P  Buchanan Daniel  Thomas Duncan C  Bishop D Timothy  Lindor Noralane M  Thibodeau Stephen N  Potter John D  Goode Ellen L;Colon CFR
Institution:Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
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.
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