A Genetic Risk Score using human chromosomal-scale length variation can predict breast cancer

Introduction: The ability to accurately predict whether a woman will develop breast cancer later in her life, should reduce the number of breast cancer deaths. Different predictive models exist for breast cancer based on family history, BRCA status, and SNP analysis. The best of these models has an accuracy (area under the receiver operating characteristic curve, AUC) of about 0.65. We have developed computational methods to characterize a genome by a small set of numbers that represent the length of segments of the chromosomes, called chromosomal-scale length variation (CSLV).Methods.We built machine learning models to differentiate between women who had breast cancer and women who did not based on their CSLV characterization. We applied this procedure to two different datasets: the UK Biobank (1,534 women with breast cancer and 4,391 women who did not) and the Cancer Genome Atlas (TCGA) 874 with breast cancer and 3,381 without.Results.We found a machine learning model that could predict breast cancer with an AUC of 0.836 95% CI(0.830.0.843) in the UK Biobank data. Using a similar approach with the TCGA data, we obtained a model with an AUC of 0.704 95%CI(0.702,0.706). Variable importance analysis indicated that no single chromosomal region was responsible for significant fraction of the model results.Conclusion.Chromosomal-scale length variation can be used to effectively predict whether or not a woman will develop breast cancer.