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

Mine S Cicek,Jane S Green,Daniel J Serie,H Banfield Younghusband,Zhu Chen,Graham Casey,Susan Parry,Duncan C Thomas,Julie M Cunningham,William R Bamlet,D Timothy Bishop,John L Hopper,Ellen L Goode,Mark A Jenkins,Robert W Haile,Fredrick Schumacher,Melissa S Derycke,Noralane M Lindor,Brenda Diergaarde,Brooke L Fridley,Roger C Green,John D Potter,Ingrid Winship,Polly A Newcomb,Theodore G Krontiris,Stephen N Thibodeau,Graeme P Young,Steven Gallinger,Loı̈c Le Marchand ,Allyson Templeton ,Finlay Macrae ,Joanne Young ,Daniel D Buchanan

doi:10.1371/journal.pone.0038175

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.

Highlights

Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in the United States
History is a consistent risk factor [2]; without colorectal cancer (CRC) family history, the lifetime risk for an individual above the age of 50 years is 5% to 6%, yet this can be as high as 20% when there are first- or second-degree relatives with CRC [3,4,5], and reaches 80% to 100% in familial syndromes [6]
MMR mutations result in a defective mismatch repair tumor phenotype manifested by absence of MMR protein expression [8,9] and DNA microsatellite instability (MSI-H)

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in the United States. 141,210 new cases and 49,380 deaths from CRC were expected in the United States in 2011 [1]. Lynch syndrome represents up to 5% of CRCs and results from germline mutations in one of several DNA mismatch repair (MMR) genes MMR mutations result in a defective mismatch repair (dMMR) tumor phenotype manifested by absence of MMR protein expression [8,9] and DNA microsatellite instability (MSI-H). Segregation analyses excluding Lynch syndrome families suggest that additional loci for CRC susceptibility exist [5]

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Results

Conclusion