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The genetic epidemiology of common hormonal cancers

The genetic epidemiology of common hormonal cancers. Deborah Thompson Centre for Cancer Genetic Epidemiology. The 15 Most Common Cancers, UK 2011 (Cancer Research UK). The 20 Most Common Cancers, UK 2011 (Cancer Research UK). Fam RR ~2 2-3 ~2 3-4. Account for 32% of UK cancers.

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The genetic epidemiology of common hormonal cancers

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  1. The genetic epidemiology of common hormonal cancers Deborah ThompsonCentre for Cancer Genetic Epidemiology

  2. The 15 Most Common Cancers, UK 2011 (Cancer Research UK)

  3. The 20 Most Common Cancers, UK 2011 (Cancer Research UK) Fam RR ~2 2-3 ~2 3-4 Account for 32% of UK cancers

  4. Example: The landscape for breast genetics in 1997

  5. Example: The landscape for breast genetics in 2014

  6. International Consortia in which CCGE plays a key role + computing / bioinformatics + laboratory resources

  7. The Collaborative Oncological Gene-environment Study (COGS) 211,115 SNPs SNP selection: BCAC OCAC PRACTICAL CIMBA “Common” • Genotyped in • >200,000 samples: • cancer cases/ctrls • BRCA1/2 carriers • GWAS follow-up • fine-mapping • candidate variants

  8. March 2013: 13 iCOGS papers, >70 new cancer loci

  9. Proportional of the Familial RR of Breast Cancer Explained Unexplained: 50% BRCA1 BRCA2 Other iCOGS estimated CHEK2 ATM PALB2 BRIP1 XRCC2 iCOGS SNPs SNPs pre-iCOGS (GWAS) TP53 PTEN LKB1 14% 5% 9% Michailidou et al 2014

  10. Proportional of the Familial RRs of: Ovarian Cancer Unexplained: 54% BRCA1 BRCA2 40% Prostate Cancer iCOGS 1% BRCA1 BRCA2 HOXB13 MMR NBS1 CHEK2 5% Unexplained: 65% RAD51C RAD51D BRIP1 2% GWAS 3% GWAS 25% iCOGS 5%

  11. 0.10 Lowest risk quintile 0.09 Quintile 2 0.08 Quintile 3 0.07 Quintile 4 0.06 Highest risk quintile 10 yr breast cancer risk Reference 0.05 0.04 0.03 0.02 0.01 0 20 25 30 35 40 45 50 55 60 65 Age (years) Ten year breast cancer risk based on 77 SNP profile 70

  12. Using our findings: the BOADICEA model • BOADICEA is a polygenic risk prediction model for familial breast and ovarian cancer. Based on cancer family-history it computes: • age-specific risks of breast and ovarian • cancer • BRCA1 and BRCA2 mutation carrier • probabilities • The user-friendly BOADICEA web application allows researchers, clinicians and members of the public to estimate risks • The web application has ~3,800 registered users worldwide • Recommended as a risk assessment tool in NICE clinical guidelines and internationally (e.g. American Cancer Society, Ontario BSP).

  13. http://ccge.medschl.cam.ac.uk/boadicea/

  14. GAME-ON OncoArray

  15. What next? DISCOVERY:OncoArray Sequencing (targeted, whole-genome) FINE-MAPPING:looking at GWAS/iCOGS risk loci in more detailed multiple independent variables within loci? linking epidemiological and functional evidence APPLICATION: extension of BOADICEA developing risk-prediction models for other cancers

  16. Acknowledgements

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