A novel colorectal cancer risk locus at 4q32.2 identified from an international genome-wide association study

Stephanie L Schmit; Fredrick R Schumacher; Christopher K Edlund; David V Conti; Leon Raskin; Flavio Lejbkowicz; Mila Pinchev; Hedy S Rennert; Mark A Jenkins; John L Hopper; Daniel D Buchanan; Noralane M Lindor; Loic Le Marchand; Steven Gallinger; Robert W Haile; Polly A Newcomb; Shu-Chen Huang; Gad Rennert; Graham Casey; Stephen B Gruber

doi:10.1093/carcin/bgu148

A novel colorectal cancer risk locus at 4q32.2 identified from an international genome-wide association study

Carcinogenesis. 2014 Nov;35(11):2512-9. doi: 10.1093/carcin/bgu148. Epub 2014 Jul 14.

Authors

Stephanie L Schmit¹, Fredrick R Schumacher¹, Christopher K Edlund¹, David V Conti¹, Leon Raskin², Flavio Lejbkowicz³, Mila Pinchev³, Hedy S Rennert³, Mark A Jenkins⁴, John L Hopper⁴, Daniel D Buchanan⁵, Noralane M Lindor⁶, Loic Le Marchand⁷, Steven Gallinger⁸, Robert W Haile⁹, Polly A Newcomb¹⁰, Shu-Chen Huang¹, Gad Rennert¹¹, Graham Casey¹, Stephen B Gruber¹²

Affiliations

¹ USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia, Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia, Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
² Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA.
³ Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel.
⁴ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
⁵ Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia.
⁶ Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA.
⁷ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
⁸ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
⁹ Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA.
¹⁰ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and.
¹¹ Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
¹² USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia, Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia, Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel [email protected].

Abstract

Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genome-wide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10(-9); nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Carcinogenesis*
Case-Control Studies
Chromosomes, Human, Pair 4 / genetics
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / pathology
Ethnicity
Female
Gene Frequency
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Genotype
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Risk Factors

Abstract

Publication types

MeSH terms

Grants and funding