Abstract
BackgroundWomen with a family history of breast cancer face considerable uncertainty about whether to pursue standard screening, intensive screening, or prophylactic surgery. Accurate and individualized risk-estimation approaches may help these women make more informed decisions. Although highly penetrant genetic variants have been associated with familial breast cancer (FBC) risk, many individuals do not carry these variants, and many carriers never develop breast cancer. Common risk variants have a relatively modest effect on risk and show limited potential for predicting FBC development. As an alternative, we hypothesized that additional genomic data types, such as gene-expression levels, which can reflect genetic and epigenetic variation, could contribute to classifying a person’s risk status. Specifically, we aimed to identify common patterns in gene-expression levels across individuals who develop FBC.MethodsWe profiled peripheral blood mononuclear cells from women with a family history of breast cancer (with or without a germline BRCA1/2 variant) and from controls. We used the support vector machines algorithm to differentiate between patients who developed FBC and those who did not. Our study used two independent datasets, a training set of 124 women from Utah (USA) and an external validation (test) set from Ontario (Canada) of 73 women (197 total). We controlled for expression variation associated with clinical, demographic, and treatment variables as well as lymphocyte markers.ResultsOur multigene biomarker provided accurate, individual-level estimates of FBC occurrence for the Utah cohort (AUC = 0.76 [0.67-84]) . Even at their lower confidence bounds, these accuracy estimates meet or exceed estimates from alternative approaches. Our Ontario cohort resulted in similarly high levels of accuracy (AUC = 0.73 [0.59-0.86]), thus providing external validation of our findings. Individuals deemed to have “high” risk by our model would have an estimated 2.4 times greater odds of developing familial breast cancer than individuals deemed to have “low” risk.ConclusionsTogether, these findings suggest that gene-expression levels in peripheral blood cells reflect genomic variation associated with breast cancer risk and that such data have potential to be used as a non-invasive biomarker for familial breast cancer risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0145-6) contains supplementary material, which is available to authorized users.
Highlights
Women with a family history of breast cancer face considerable uncertainty about whether to pursue standard screening, intensive screening, or prophylactic surgery
Controls were of three types: individuals with a family history of breast cancer who themselves did not develop breast cancer by age 55 or greater; individuals with no family history of breast cancer who did not develop breast cancer; and individuals with no family history of breast cancer who did develop breast cancer
Our gene expression-based estimates of familial breast cancer (FBC) development were consistently higher for women from FBC families who had developed cancer than for any subset of controls (Fig. 1a), attaining an Area under receiver operating characteristic curve (AUC) value of 0.76
Summary
Women with a family history of breast cancer face considerable uncertainty about whether to pursue standard screening, intensive screening, or prophylactic surgery. Many women with a family history of breast cancer, including many who carry BRCA1 or BRCA2 mutations, never develop breast cancer. Screening and prevention resources could be focused on those women who carry the highest risk for familial breast cancer (FBC), while women with a lower risk could be spared the risks and inconveniences of prophylaxis or intensive screening. Such an approach would be non-invasive and provide estimates of risk that are tailored to each individual
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