title: Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis.
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.
authors.affiliation: Epidemiology Department, University of Washington, Seattle, WA 98195, USA.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Amanda I
authors.initials: AI
authors.lastname: Phipps
authors.affiliation: Epidemiology Department, University of Washington, Seattle, WA 98195, USA.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Passarelli
authors.affiliation: Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Public Health Sciences Division , Fred Hutchinson Cancer Research Center , Seattle , WA 98109 , USA.
authors.forename: Tabitha A
authors.initials: TA
authors.lastname: Harrison
authors.affiliation: Public Health Sciences Division , Fred Hutchinson Cancer Research Center , Seattle , WA 98109 , USA.
authors.forename: Jihyoun
authors.initials: J
authors.lastname: Jeon
authors.affiliation: Public Health Sciences Division , Fred Hutchinson Cancer Research Center , Seattle , WA 98109 , USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Hutter
authors.affiliation: Division of Cancer Epidemiology and Genetics , National Cancer Institute , National Institutes of Health , Bethesda , MD 20892 , USA.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.|German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: Division of Research , Kaiser Permanente Medical Care Program of Northern California , Oakland , CA 94612 , USA.
authors.forename: Bette J
authors.initials: BJ
authors.lastname: Caan
authors.affiliation: Epidemiology Research Program , American Cancer Society , Atlanta , GA 30303 , USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Campbell
authors.affiliation: Division of Cancer Epidemiology , Unit of Genetic Epidemiology , German Cancer Research Center (DKFZ) , Heidelberg 69120 , Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Division of Cancer Epidemiology and Genetics , National Cancer Institute , National Institutes of Health , Bethesda , MD 20892 , USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Institute of Cancer and Genetics , School of Medicine , Cardiff University , Cardiff CF14 4XN , UK.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
authors.affiliation: Public Health Sciences Division , Fred Hutchinson Cancer Research Center , Seattle , WA 98109 , USA.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Curtis
authors.affiliation: Translational Genomics Research Institute , Phoenix , AZ 85004 , USA.
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.affiliation: MRC Clinical Trials Unit , University College London , Aviation House , London WC2B 6NH , UK.
authors.forename: David
authors.initials: D
authors.lastname: Fisher
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Harvard School of Public Health , Boston , MA 02115 , USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Gala
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.|Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.affiliation: Division of Epidemiology , Department of Population Health , New York University School of Medicine , New York , NY 10016 , USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.affiliation: German Cancer Consortium (DKTK) , Heidelberg 69120 , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmeister
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.|Biostatistics Department, University of Washington, Seattle, WA 98195, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.affiliation: Division of Cancer Epidemiology , Unit of Genetic Epidemiology , German Cancer Research Center (DKFZ) , Heidelberg 69120 , Germany.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jacobs
authors.affiliation: Division of Clinical Epidemiology and Aging Research , German Cancer Research Center (DKFZ) , Heidelberg 69120 , Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Jansen
authors.affiliation: MRC Clinical Trials Unit , University College London , Aviation House , London WC2B 6NH , UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.affiliation: Division of Cancer Epidemiology , Unit of Genetic Epidemiology , German Cancer Research Center (DKFZ) , Heidelberg 69120 , Germany.
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Kap
authors.affiliation: Gray Institute for Radiation Oncology and Biology , University of Oxford , Oxford OX3 7DQ , UK.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Maughan
authors.affiliation: Epidemiology Department, University of Washington, Seattle, WA 98195, USA.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.|Centre for Public Health Research, Massey University, Wellington 6140, New Zealand.
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: Department of Medicine and Epidemiology , University of Pittsburgh Medical Center , Pittsburgh , PA 15213 , USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schoen
authors.affiliation: Division of Cancer Control and Population Sciences , National Cancer Institute , National Institutes of Health , Bethesda , MD 20892 , USA , and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Seminara
authors.affiliation: Department of Internal Medicine , University of Utah Health Sciences Center , Salt Lake City , UT 84132 , USA.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
authors.affiliation: Institute of Cancer and Genetics , School of Medicine , Cardiff University , Cardiff CF14 4XN , UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: West
authors.affiliation: Epidemiology Department, University of Washington, Seattle, WA 98195, USA.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: White
authors.affiliation: Epidemiology Department, University of Washington, Seattle, WA 98195, USA.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Epidemiology Department, University of Washington, Seattle, WA 98195, USA.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies