title: Discovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients.
abstract: BACKGROUND
  Ovarian cancer remains a significant public health burden, with the highest mortality rate of all the gynecological cancers. This is attributable to the late stage at which the majority of ovarian cancers are diagnosed, coupled with the low and variable response of advanced tumors to standard chemotherapies. To date, clinically useful predictors of treatment response remain lacking. Identifying the genetic determinants of ovarian cancer survival and treatment response is crucial to the development of prognostic biomarkers and personalized therapies that may improve outcomes for the late-stage patients who comprise the majority of cases.
  
  
  METHODS
  To identify constitutional genetic variations contributing to ovarian cancer mortality, we systematically investigated associations between germline polymorphisms and ovarian cancer survival using data from The Cancer Genome Atlas Project (TCGA). Using stage-stratified Cox proportional hazards regression, we examined >650,000 SNP loci for association with survival. We additionally examined whether the association of significant SNPs with survival was modified by somatic alterations.
  
  
  RESULTS
  Germline polymorphisms at rs4934282 (AGAP11/C10orf116) and rs1857623 (DNAH14) were associated with stage-adjusted survival (p= 1.12e-07 and 1.80e-07, FDR q= 1.2e-04 and 2.4e-04, respectively). A third SNP, rs4869 (C10orf116), was additionally identified as significant in the exome sequencing data; it is in near-perfect LD with rs4934282. The associations with survival remained significant when somatic alterations.
  
  
  CONCLUSIONS
  Discovery analysis of TCGA data reveals germline genetic variations that may play a role in ovarian cancer survival even among late-stage cases. The significant loci are located near genes previously reported as having a possible relationship to platinum and taxol response. Because the variant alleles at the significant loci are common (frequencies for rs4934282 A/C alleles = 0.54/0.46, respectively; rs1857623 A/G alleles = 0.55/0.45, respectively) and germline variants can be assayed noninvasively, our findings provide potential targets for further exploration as prognostic biomarkers and individualized therapies.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA. rbraun@northwestern.edu
authors.forename: Rosemary
authors.initials: R
authors.lastname: Braun
authors.forename: Richard
authors.initials: R
authors.lastname: Finney
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yan
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Michael
authors.initials: M
authors.lastname: Edmonson
authors.forename: Daoud
authors.initials: D
authors.lastname: Meerzaman
authors.forename: Kenneth
authors.initials: K
authors.lastname: Buetow
mesh_terms: D018572:Disease-Free Survival; D059472:Exome / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D005819:Genetic Markers; D018095:Germ-Line Mutation; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D020641:Polymorphism, Single Nucleotide; D015996:Survival Rate
chemical_list: D005819:Genetic Markers
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