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Carcinogenesis. 2016 Jan;37(1):87-95. doi: 10.1093/carcin/bgv161. Epub 2015 Nov 19.

Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis.

Author information

1
Epidemiology Department, University of Washington, Seattle, WA 98195, USA.
2
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
3
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
4
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
5
Public Health Sciences Division , Fred Hutchinson Cancer Research Center , Seattle , WA 98109 , USA.
6
Division of Cancer Epidemiology and Genetics , National Cancer Institute , National Institutes of Health , Bethesda , MD 20892 , USA.
7
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
8
German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
9
Division of Research , Kaiser Permanente Medical Care Program of Northern California , Oakland , CA 94612 , USA.
10
Epidemiology Research Program , American Cancer Society , Atlanta , GA 30303 , USA.
11
Division of Cancer Epidemiology , Unit of Genetic Epidemiology , German Cancer Research Center (DKFZ) , Heidelberg 69120 , Germany.
12
Institute of Cancer and Genetics , School of Medicine , Cardiff University , Cardiff CF14 4XN , UK.
13
Translational Genomics Research Institute , Phoenix , AZ 85004 , USA.
14
MRC Clinical Trials Unit , University College London , Aviation House , London WC2B 6NH , UK.
15
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
16
Harvard School of Public Health , Boston , MA 02115 , USA.
17
Harvard School of Public Health, Boston, MA 02115, USA.
18
Division of Epidemiology , Department of Population Health , New York University School of Medicine , New York , NY 10016 , USA.
19
German Cancer Consortium (DKTK) , Heidelberg 69120 , Germany.
20
Biostatistics Department, University of Washington, Seattle, WA 98195, USA.
21
Division of Clinical Epidemiology and Aging Research , German Cancer Research Center (DKFZ) , Heidelberg 69120 , Germany.
22
Gray Institute for Radiation Oncology and Biology , University of Oxford , Oxford OX3 7DQ , UK.
23
Centre for Public Health Research, Massey University, Wellington 6140, New Zealand.
24
Department of Medicine and Epidemiology , University of Pittsburgh Medical Center , Pittsburgh , PA 15213 , USA.
25
Division of Cancer Control and Population Sciences , National Cancer Institute , National Institutes of Health , Bethesda , MD 20892 , USA , and.
26
Department of Internal Medicine , University of Utah Health Sciences Center , Salt Lake City , UT 84132 , USA.

Abstract

Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10(-10) and HR = 1.8, P = 3.7×10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest.

PMID:
26586795
PMCID:
PMC4715234
DOI:
10.1093/carcin/bgv161
[Indexed for MEDLINE]
Free PMC Article

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