Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Research output: Contribution to journalJournal articleResearchpeer-review

  • Stacey J Winham
  • Ailith Pirie
  • Yian Ann Chen
  • Melissa C Larson
  • Zachary C Fogarty
  • Madalene A Earp
  • Hoda Anton-Culver
  • Elisa V Bandera
  • Daniel W Cramer
  • Jennifer A Doherty
  • Marc T Goodman
  • Jacek Gronwald
  • Beth Y Karlan
  • Douglas A Levine
  • Usha Menon
  • Roberta B Ness
  • Celeste L Pearce
  • Tanja Pejovic
  • Mary Anne Rossing
  • Nicolas Wentzensen
  • Yukie T Bean
  • Maria Bisogna
  • Louise A Brinton
  • Michael E Carney
  • Julie M Cunningham
  • Cezary Cybulski
  • Anna deFazio
  • Ed M Dicks
  • Robert P Edwards
  • Simon A Gayther
  • Aleksandra Gentry-Maharaj
  • Martin Gore
  • Edwin S Iversen
  • Allan Jensen
  • Sharon E Johnatty
  • Jenny Lester
  • Hui-Yi Lin
  • Jolanta Lissowska
  • Jan Lubinski
  • Janusz Menkiszak
  • Francesmary Modugno
  • Kirsten B Moysich
  • Irene Orlow
  • Malcolm C Pike
  • Susan J Ramus
  • Honglin Song
  • Kathryn L Terry
  • Pamela J Thompson
  • Jonathan P Tyrer
  • David J Van Den Berg
  • Robert A Vierkant
  • Allison F Vitonis
  • Christine Walsh
  • Lynne R Wilkens
  • Anna H Wu
  • Hannah Yang
  • Argyrios Ziogas
  • Andrew Berchuck
  • Georgia Chenevix-Trench
  • Joellen M Schildkraut
  • Jennifer Permuth-Wey
  • Catherine M Phelan
  • Paul P D Pharoah
  • Brooke L Fridley
  • Thomas A Sellers
  • Ellen L Goode

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
JournalCancer Epidemiology Biomarkers and Prevention
Volume25
Issue number3
Pages (from-to)446-454
Number of pages9
ISSN1055-9965
DOIs
Publication statusPublished - 2016

ID: 179163513