Prediction of breast cancer risk based on profiling with common genetic variants

Abstract

Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.

Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.

Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.

Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.

Figure 1.

Distribution of the number of breast cancer risk alleles (A) and polygenic risk score residuals after adjusting the polygenic risk score (PRS) for study and seven principal components (B), in 33 673 breast cancer cases and 33 381 control women of European origin. The PRS approximated a normal distribution in both breast cancer cases and control women. The mean PRS was 0.69 for breast cancer cases and 0.49 for control women. PRS residuals are standardized Pearson’s residuals calculated after regression of the score on seven principal components.

Figure 2.

Association between the polygenic risk score (PRS) and breast cancer risk in women of European origin for (A) all breast cancers, (B) estrogen receptor (ER)–positive disease, and (C) ER-negative disease. Odds ratios are for different percentiles of the PRS relative to the middle quintile (40% to 60%) of the PRS. Odds ratios and 95% confidence intervals are shown. Regular lines denote the observed estimates, and dotted lines the theoretical estimates under a multiplicative polygenic model with a standard deviation of the PRS of 0.45 for all breast cancer, 0.50 for ER-positive breast cancer, and 0.38 for ER-negative breast cancer, as derived from the estimated effect sizes and allele frequencies/haplotype frequencies for each locus. PRS = polygenic risk score.

Figure 3.

Cumulative and 10-year absolute risks of developing breast cancer for women of European origin by percentiles of the polygenic risk score (PRS). Cumulative absolute risk of developing breast cancer for (A) all breast cancers, (B) estrogen receptor (ER)–positive disease, and (C) ER-negative disease by percentiles of the PRS; and 10-year absolute risk of developing breast cancer for (D) all breast cancers, (E) ER-positive disease, and (F) ER-negative disease. Note different scales and PRS categories in the different panels. The red line shows the 2.4% risk threshold corresponding to the risk for women age 47 years who were eligible for screening, calculated as described in the Supplementary Methods (available online). Absolute risks were calculated using the PRS relative risks estimated as described in the Supplementary Methods (available online), and breast cancer incident rates and mortality from other causes obtained from the UK National Office for Statistics. For subtype-specific disease, the absolute risk for women in a particular PRS category for ER-positive disease and another PRS category for ER-negative disease were calculated. Information on proportions of tumors by ER status was obtained from the West Midlands Registry.

Figure 4.

Cumulative and 10-year absolute risks of developing breast cancer for women of European origin with and without a family history of breast cancer by percentiles of the polygenic risk score (PRS). Cumulative absolute risk of developing breast cancer for women (A) without a family history and (B) with a family history, and 10-year absolute risk of developing breast cancer for women (C) without a family history, and (D) with a family history of breast cancer by percentiles of the PRS. The red line shows the 2.4% risk threshold corresponding to the risk for women age 47 years who were eligible for screening. Absolute risks were calculated using PRS relative risks estimated as described in Methods, and breast cancer incident rates and mortality from other causes obtained from the UK National Office for Statistics.