The genetic epidemiology of common hormonal cancers
Deborah ThompsonCentre for Cancer Genetic Epidemiology
The 15 Most Common Cancers, UK 2011 (Cancer Research UK)
Fam RR~2
2-3
~2
3-4
The 20 Most Common Cancers, UK 2011 (Cancer Research UK)
Account for 32% of UK cancers
0.000001 0.00001 0.0001 0.001 0.01 0.11
10
Allele frequency
Rela
tive
Risk
BRCA1
BRCA2TP53
? ATM ?
PTEN
Example: The landscape for breast genetics in 1997
0.000001 0.00001 0.0001 0.001 0.01 0.1 11
10
Allele frequency
Rela
tive
Risk
BRCA1
BRCA2TP53
PALB2
CHEK2 ATM
CDH1
STK11
PTEN
Risk SNPs
Example: The landscape for breast genetics in 2014
International Consortia in which CCGE plays a key roleCancer site Consortium No. studies CCGE involvement
Breast BCAC 90 SEARCH study, SIBS study;Genetic + phenotypic data management, QC + statistical analyses, website
Prostate PRACTICAL 78 SEARCH study;Genetic + phenotypic data management, QC + statistical analyses, website
BRCA1/2 carriers CIMBA 65 EMBRACE study, UKFOCR study; Genetic + phenotypic data management, QC + statistical analyses, website
Ovarian OCAC 50 SEARCH study, UKFOCR study, RMH study;Genetic data management, QC + statistical analyses, website
Endometrial ECAC 16 SEARCH study; QC + statistical analyses
+ computing / bioinformatics + laboratory resources
The Collaborative Oncological Gene-environment Study (COGS)
• GWAS follow-up• fine-mapping• candidate variants
211,115 SNPs
SNP selection:BCAC
OCAC
PRACTICAL
CIMBA
“Common”
Genotyped in >200,000 samples:• cancer cases/ctrls • BRCA1/2 carriers
March 2013: 13 iCOGS papers, >70 new cancer loci
Unexplained: 50%
BRCA1BRCA2CHEK2
ATMPALB2BRIP1XRCC2
TP53PTENLKB1
SNPs pre-iCOGS
(GWAS)
Proportional of the Familial RR of Breast Cancer Explained
iCOGSSNPs
Other iCOGSestimated
9%5%
14%
Michailidou et al 2014
Proportional of the Familial RRs of:
Unexplained: 54%
BRCA1BRCA240%
GWAS3%
iCOGS 1% RAD51C
RAD51DBRIP12%
Ovarian Cancer
Unexplained: 65%
BRCA1BRCA2HOXB13MMRNBS1CHEK25%
GWAS25%
iCOGS5%
Prostate Cancer
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
20 25 30 35 40 45 50 55 60 65
10 y
r bre
ast c
ance
r ris
k
Age (years)
Lowest risk quintile
Quintile 2
Quintile 3
Quintile 4
Highest risk quintile
Reference
Ten year breast cancer risk based on 77 SNP profile
70
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).
Using our findings: the BOADICEA model
http://ccge.medschl.cam.ac.uk/boadicea/
GAME-ON OncoArray
OncoChip600K
beadtypes
GWAS Backbone
250KIllumina Core
Common Content – 40K Fine-mapping of common cancer susceptibility loci
Ancestry Informative MarkersCross-Site meta analysis
Pharmacogenetic components Quantitative traits
Other cancers published GWAS variantsChromosome X and mitochondrial DNA variants
Cancer Specific Variants ~320k
ProstateBreast
OvarianLung
BRCA1/2 carriersColon
What next?
DISCOVERY: OncoArraySequencing (targeted, whole-
genome)
FINE-MAPPING: looking at GWAS/iCOGS risk loci in more detailedmultiple independent variables
within loci?linking epidemiological and
functional evidence
APPLICATION: extension of BOADICEA developing risk-prediction
models for other cancers
Acknowledgements