Incidence of breast cancer and its subtypes in relation to individual and multiple low-penetrance genetic susceptibility loci.
BACKGROUND
There is limited evidence on how the risk of breast cancer and its subtypes depend on low-penetrance susceptibility loci, individually or in combination.


OBJECTIVE
To analyze breast cancer risk, overall and by tumor subtype, in relation to 14 individual single-nucleotide polymorphisms (SNPs) previously linked to the disease, and in relation to a polygenic risk score.


METHODS
Study of 10,306 women with breast cancer (mean age at diagnosis, 58 years) and 10,393 women without breast cancer who in 2005-2008 provided blood samples for genotyping in a large prospective study of UK women; and meta-analysis of these results and of other published results.


METHODS
Estimated per-allele odds ratio (OR) for individual SNPs, and cumulative incidence of breast cancer to age 70 years in relation to a polygenic risk score based on the 4, 7, or 10 SNPs most strongly associated with risk.


RESULTS
Odds ratios for breast cancer were greatest for FGFR2-rs2981582 and TNRC9-rs3803662 and, for these 2 SNPs, were significantly greater for estrogen receptor (ER)-positive than for ER-negative disease, both in our data and in meta-analyses of all published data (pooled per-allele ORs [95% confidence intervals] for ER-positive vs ER-negative disease: 1.30 [1.26-1.33] vs 1.05 [1.01-1.10] for FGFR2; interaction P < .001; and 1.24 [1.21-1.28] vs 1.12 [1.07-1.17] for TNRC9; interaction P < .001). The next strongest association was for 2q-rs13387042, for which the per-allele OR was significantly greater for bilateral than unilateral disease (1.39 [1.21-1.60] vs 1.15 [1.11-1.20]; interaction P = .008) and for lobular than ductal tumors (1.35 [1.23-1.49] vs 1.10 [1.05-1.15]; interaction P < .001). The estimated cumulative incidence (95% confidence interval) of breast cancer to age 70 years among women in the top and bottom fifths of a polygenic risk score based on 7 SNPs was 8.8% (8.3%-9.4%) and 4.4% (4.2%-4.8%), respectively. For ER-positive disease the corresponding risks were 7.4% (6.9%-8.0%) and 3.4% (3.1%-3.8%), respectively; while for ER-negative disease they were 1.4% (1.2%-1.6%) and 1.0% (0.8%-1.2%). The findings did not differ materially according to the number of SNPs included in the polygenic risk model.


CONCLUSIONS
The polygenic risk score was substantially more predictive of ER-positive than of ER-negative breast cancer, particularly for absolute risk.
Reeves
Gillian K
GK
Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom. gill.reeves@ceu.ox.ac.uk
Travis
Ruth C
RC
Green
Jane
J
Bull
Diana
D
Tipper
Sarah
S
Baker
Krys
K
Beral
Valerie
V
Peto
Richard
R
Bell
John
J
Zelenika
Diana
D
Lathrop
Mark
M
D000368:Aged; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006609:High Mobility Group Proteins; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone / Q000235:genetics; D015534:Trans-Activators; D006113:United Kingdom / Q000453:epidemiology; D014481:United States / Q000453:epidemiology
D051017:Apoptosis Regulatory Proteins; D006609:High Mobility Group Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C521752:TOX3 protein, human; D015534:Trans-Activators; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2