Women who carry BRCA2 mutations have an increased risk
of breast cancer that varies widely. To identify common
genetic variants that modify the breast cancer risk
associated with BRCA2 mutations, we have built upon
our previous work in which we examined genetic variants
across the genome in relation to breast cancer risk among
BRCA2 mutation carriers. Using a custom genotyping
platform with 211,155 genetic variants known as single
nucleotide polymorphisms (SNPs), we genotyped 3,881
women who had breast cancer and 4,330 women without
breast cancer, which represents the largest possible,
international collection of BRCA2 mutation carriers. We
identified that a SNP located at 6p24 in the genome was
associated with lower risk of breast cancer. Importantly,
this SNP was not associated with breast cancer in BRCA1
mutation carriers or in a general population of women,
indicating that the breast cancer association with this SNP
might be specific to BRCA2 mutation carriers. Combining
this BRCA2-specific SNP with 13 other breast cancer risk
SNPs also known to modify risk in BRCA2 mutation carriers,
we were able to derive a risk prediction model that could
be useful in helping women with BRCA2 mutations weigh
their risk-reduction strategy options.
Conceived and designed the experiments: P Hall, FJ Couch, J Simard, D
Altshuler, DF Easton, G Chenevix-Trench, AC Antoniou, K Offit. Performed the experiments: MM Gaudet, KB Kuchenbaecker, J Vijai, RJ
Klein, T Kirchhoff. Analyzed the data: MM Gaudet, KB Kuchenbaecker,
J Vijai, RJ Klein, L McGuffog, D Barrowdale, AM Dunning, J Simard, D
Altshuler, DF Easton, AC Antoniou, K Offit. Contributed reagents/
materials/analysis tools: L McGuffog, D Barrowdale, AM Dunning, A Lee,
J Dennis, S Healey, E Dicks, P Soucy, OM Sinilnikova, VS Pankratz, X
Wang, RC Eldridge, DC Tessier, D Vincent, F Bacot, FBL Hogervorst, S
Peock, D Stoppa-Lyonnet, P Peterlongo, RK Schmutzler, KL Nathanson,
M Piedmonte, CF Singer, M Thomassen, TvO Hansen, SL Neuhausen, I
Blanco, MH Greene, J Garber, JN Weitzel, IL Andrulis, DE Goldgar, E
D’Andrea, T Caldes, H Nevanlinna, A Osorio, EJ van Rensburg, A
Arason, G Rennert, AMW van den Ouweland, AH van der Hout, CM
Kets, CM Aalfs, JT Wijnen, MGEM Ausems, D Frost, S Ellis, E Fineberg,
R Platte, DG Evans, C Jacobs, J Adlard, M Tischkowitz, ME Porteous, F
Damiola, L Golmard, L Barjhoux, M Longy, M Belotti, SF Ferrer, S
Mazoyer, AB Spurdle, S Manoukian, M Barile, M Genuardi, N Arnold, A
Meindl, C Sutter, B Wappenschmidt, SM Domchek, G Pfeiler, E
Friedman, UB Jensen, M Robson, S Shah, C Lazaro, PL Mai, J Benitez,
MC Southey, MK Schmidt, PA Fasching, J Peto, MK Humphreys, Q
Wang, K Michailidou, EJ Sawyer, B Burwinkel, P Gue´nel, SE Bojesen, RL
Milne, H Brenner, M Lochmann, K Aittoma¨ ki, T Do¨rk, S Margolin, A
Mannermaa, D Lambrechts, J Chang-Claude, P Radice, GG Giles, CA
Haiman, R Winqvist, P Devillee, M Garcı´a-Closas, N Schoof, MJ
Hooning, A Cox, PDP Pharoah, A Jakubowska, N Orr, A Gonza´lez-Neira,
G Pita, MR Alonso, P Hall, FJ Couch, DF Easton, G Chenevix-Trench,
AC Antoniou, K Offit. Wrote the paper: MM Gaudet, KB Kuchenbaecker,
J Vijai, RJ Klein, AC Antoniou, K Offit.
Figure S1 Cluster plots for SNPs (A.) rs9348512, (B.) rs619373,
and (C.) rs184577.
Figure S2 Multidimensional scaling plots of the top two
principal components of genomic ancestry of all eligible BRCA2
iCOGS samples plotted with the HapMap CEU, ASI, and YRI
samples: (A.) samples from Finland and BRCA2 6174delT carriers
highlighted, and (B.) samples, indicated in red, with .19% non-
European ancestry were excluded.
Figure S3 Quantile–quantile plot comparing expected and
observed distributions of P-values. Results displayed (A) for the
complete sample, (B) after excluding samples from the GWAS
discovery stage, and (C) for the complete sample and a set of SNPs
from the iCOGS array that were selected independent from the
results of the BRCA2 mutation carriers.
Figure S4 Manhattan plot of P-values by chromosomal position
for 18,086 SNPs selected on the basis of a previously published
genome-wide association study of BRCA2 mutation carriers. Breast
cancer associations results based on 4,330 breast cancer cases and
3,881 unaffected BRCA2 carriers.
Figure S5 Forest plot of the country-specific, per-allele hazard
ratios (HR) and 95% confidence intervals for the association
between breast cancer and rs9348512 genotypes.
Figure S6 Forest plot of the country-specific, per-allele hazard
ratios (HR) and 95% confidence intervals for the association with
breast cancer for (A.) rs619373 and (B.) rs184577 genotypes.
Table S1 Quality control filtering steps for BRCA2 mutation
carriers and SNPs on the COGs array.
Table S2 Description of breast cancer affected and unaffected
BRCA2 carriers included in the final analysis of the COGs array
SNPs.
Table S3 Breast cancer hazards ratios (HR) and 95% confidence
intervals (CI) for all SNPs with P,1023 in a 500 Mb region
around rs9348512 on 6p24 among BRCA2 mutation carriers.
Table S4 Associations with SNPs at 6p24, FGF13 and 2p22 and
breast and ovarian cancer risk using a competing risk analysis
model.