Simple Summary Genetic variants explaining approximately 40% of familial breast cancer risk have been identified, thus leaving a significant fraction of the heritability of this disease still... Show moreSimple Summary Genetic variants explaining approximately 40% of familial breast cancer risk have been identified, thus leaving a significant fraction of the heritability of this disease still unexplained. The exact nature of this missing fraction is unknown; more extensive sequencing efforts could potentially identify new moderate-penetrance breast cancer risk alleles. The aim of this study was to perform a large-scale whole-exome sequencing study, followed by a targeted validation, in breast cancer patients and healthy women of European descent. We identified 20 novel genes with modest evidence of association (p-value < 0.05) for either overall or subtype-specific breast cancer; however, much larger studies are needed to confirm the exact role of these genes in susceptibility to breast cancer. Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes. Show less
Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new... Show moreIdentifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis. Show less
Wojtowicz, E.E.; Lechman, E.R.; Hermans, K.G.; Schoof, E.M.; Wienholds, E.; Isserlin, R.; ... ; Haan, G. de 2016
