Pritzker School of Medicine
Published July 27, 2016 | Version v1
Journal article Open

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Creators

  • 1. University of Cambridge
  • 2. QIMR Berghofer Medical Research Institute
  • 3. Chapel Allerton Hospital
  • 4. University of Iceland
  • 5. Mount Sinai Hospital
  • 6. University of Texas MD Anderson Cancer Center
  • 7. Centre Léon Bérard
  • 8. Institut Curie
  • 9. Spanish National Cancer Centre
  • 10. Medical University of Vienna
  • 11. Vejle Hospital
  • 12. Istituto Europeo di Oncologia
  • 13. Royal Devon & Exeter Hospital
  • 14. Hospital Clinico San Carlos
  • 15. University of Pisa
  • 16. Peter MacCallum Cancer Centre
  • 17. University of California, San Francisco
  • 18. Ghent University
  • 19. University of Chicago

Description

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

Data availability

All relevant data are within the paper and its Supporting Information files. The raw data are available through application to the CIMBA Data Access Coordinating Committee (http://apps.ccge.medschl.cam.ac.uk/consortia/cimba/index.html) for researchers who meet the criteria for access to confidential data.

Files

journal.pone.0158801.pdf

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Additional details

Identifiers

DOI
10.1371/journal.pone.0158801
Other
oai:uchicago.tind.io:7075

Funding

Cancer Research – UK
C12292/A11174
Cancer Research – UK
C1287/A10118
MRC
Advanced Studentship award

UChicago Information

Division(s)
Biological Sciences Division, Pritzker School of Medicine
Department(s)
Medicine