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Cancer Epidemiol Biomarkers Prev. 2016 Mar;25(3):446-54. doi: 10.1158/1055-9965.EPI-15-0240. Epub 2016 Jan 8.

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer.

Author information

1
Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
2
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
3
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
4
Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota.
5
Department of Epidemiology, University of California Irvine, Irvine, California.
6
Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey.
7
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
8
Section of Biostatistics and Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
9
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
10
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
11
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
12
Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
13
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
14
Gynaecological Cancer Research Centre, Department of Women's Cancer, Institute for Women's Health, University College London, London, United Kingdom.
15
The University of Texas School of Public Health, Houston, Texas.
16
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
17
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
18
Department of Epidemiology, University of Washington, Seattle, Washington. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
19
Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.
20
Department of Obstectrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
21
Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, Minnesota.
22
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical Academy, Szczecin, Poland.
23
Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia. Center for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, Australia.
24
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
25
Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
26
Gynecological Oncology Unit, The Royal Marsden Hospital, London, United Kingdom.
27
Department of Statistical Science, Duke University, Durham, North Carolina.
28
Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
29
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
30
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland.
31
Department of Surgical Gynecology and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland.
32
Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania. Womens Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
33
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
34
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
35
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
36
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
37
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
38
Department of Epidemiology, Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine, Irvine, California.
39
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
40
Public Health Services, University of Virginia, Charlottesville, Virginia.
41
Kansas IDeA Network of Biomedical Research Excellence Bioinformatics Core, University of Kansas Cancer Center, Kansas City, Kansas.
42
Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota. egoode@mayo.edu.

Abstract

BACKGROUND:

While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC).

METHODS:

The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped).

RESULTS:

No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01).

CONCLUSIONS:

Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed.

IMPACT:

This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54. ©2016 AACR.

PMID:
26747452
PMCID:
PMC4779669
DOI:
10.1158/1055-9965.EPI-15-0240
[Indexed for MEDLINE]
Free PMC Article

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