Investigation of exomic variants associated with overall survival in ovarian cancer

The Australian Ovarian Cancer Study Group, ACS Investigators

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 independentEOCstudies (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 EOCsurvival 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.

Original languageEnglish (US)
Pages (from-to)446-454
Number of pages9
JournalCancer Epidemiology Biomarkers and Prevention
Volume25
Issue number3
DOIs
StatePublished - Mar 1 2016

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Ovarian Neoplasms
Survival
Exome
Genes
Autophagy
Tumor Biomarkers
Genetic Markers
Single Nucleotide Polymorphism
Meta-Analysis
Ovarian epithelial cancer
Genome
Apoptosis

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Investigation of exomic variants associated with overall survival in ovarian cancer. / The Australian Ovarian Cancer Study Group; ACS Investigators.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 25, No. 3, 01.03.2016, p. 446-454.

Research output: Contribution to journalArticle

The Australian Ovarian Cancer Study Group ; ACS Investigators. / Investigation of exomic variants associated with overall survival in ovarian cancer. In: Cancer Epidemiology Biomarkers and Prevention. 2016 ; Vol. 25, No. 3. pp. 446-454.
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title = "Investigation of exomic variants associated with overall survival in ovarian cancer",
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 independentEOCstudies (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 EOCsurvival 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.",
author = "{The Australian Ovarian Cancer Study Group} and {ACS Investigators} and Winham, {Stacey J.} and Ailith Pirie and Chen, {Yian Ann} and Larson, {Melissa C.} and Fogarty, {Zachary C.} and Earp, {Madalene A.} and Hoda Anton-Culver and Bandera, {Elisa V.} and Daniel Cramer and Doherty, {Jennifer A.} and Goodman, {Marc T.} and Jacek Gronwald and Karlan, {Beth Y.} and Kjaer, {Susanne K.} and Levine, {Douglas A.} and Usha Menon and Ness, {Roberta B.} and Pearce, {Celeste L.} and Tanja Pejovic and Rossing, {Mary Anne} and Nicolas Wentzensen and Bean, {Yukie T.} and Maria Bisogna and Brinton, {Louise A.} and Carney, {Michael E.} and Cunningham, {Julie M.} and Cezary Cybulski and Anna DeFazio and Dicks, {Ed M.} and Edwards, {Robert P.} and Gayther, {Simon A.} and Aleksandra Gentry-Maharaj and Martin Gore and Iversen, {Edwin S.} and Allan Jensen and Johnatty, {Sharon E.} and Jenny Lester and Lin, {Hui Yi} and Jolanta Lissowska and Jan Lubinski and Janusz Menkiszak and Francesmary Modugno and Moysich, {Kirsten B.} and Irene Orlow and Pike, {Malcolm C.} and Ramus, {Susan J.} and Honglin Song and Terry, {Kathryn L.} and Thompson, {Pamela J.} and Tyrer, {Jonathan P.}",
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T1 - Investigation of exomic variants associated with overall survival in ovarian cancer

AU - The Australian Ovarian Cancer Study Group

AU - ACS Investigators

AU - Winham, Stacey J.

AU - Pirie, Ailith

AU - Chen, Yian Ann

AU - Larson, Melissa C.

AU - Fogarty, Zachary C.

AU - Earp, Madalene A.

AU - Anton-Culver, Hoda

AU - Bandera, Elisa V.

AU - Cramer, Daniel

AU - Doherty, Jennifer A.

AU - Goodman, Marc T.

AU - Gronwald, Jacek

AU - Karlan, Beth Y.

AU - Kjaer, Susanne K.

AU - Levine, Douglas A.

AU - Menon, Usha

AU - Ness, Roberta B.

AU - Pearce, Celeste L.

AU - Pejovic, Tanja

AU - Rossing, Mary Anne

AU - Wentzensen, Nicolas

AU - Bean, Yukie T.

AU - Bisogna, Maria

AU - Brinton, Louise A.

AU - Carney, Michael E.

AU - Cunningham, Julie M.

AU - Cybulski, Cezary

AU - DeFazio, Anna

AU - Dicks, Ed M.

AU - Edwards, Robert P.

AU - Gayther, Simon A.

AU - Gentry-Maharaj, Aleksandra

AU - Gore, Martin

AU - Iversen, Edwin S.

AU - Jensen, Allan

AU - Johnatty, Sharon E.

AU - Lester, Jenny

AU - Lin, Hui Yi

AU - Lissowska, Jolanta

AU - Lubinski, Jan

AU - Menkiszak, Janusz

AU - Modugno, Francesmary

AU - Moysich, Kirsten B.

AU - Orlow, Irene

AU - Pike, Malcolm C.

AU - Ramus, Susan J.

AU - Song, Honglin

AU - Terry, Kathryn L.

AU - Thompson, Pamela J.

AU - Tyrer, Jonathan P.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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 independentEOCstudies (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 EOCsurvival 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.

AB - 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 independentEOCstudies (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 EOCsurvival 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.

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