Deciphering the genetic background in unexplained high-risk breast cancer families : integration of somatic data to unravel heredity

Breast cancer is a heterogeneous disease for which the existence of monogenic and polygenic models of inheritance have been described for decades. Multigene panel testing is useful for the diagnosis of monogenic breast cancer predisposition, allowing to simultaneously sequence a large number of genes of several patients. However, this approach increases the identification of variants of unknown significance (VUS) that cannot be used in clinical decision-making. We first performed a systematic review and meta-analysis of studies conducting multigene panel testing on germline DNA of women with familial breast cancer. We found that using current panels, the probability of detecting a VUS is significantly higher than the probability of detecting a pathogenic variant. BRCA1 and BRCA2, the two most extensively studied breast cancer predisposing genes until now, were the only genes presenting the opposite trend. Reclassification of VUS in the other more recently identified genes is therefore required to drastically reduce the number of families for which genetic counselors are not able to draw a conclusion. Using a cohort of 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1, BRCA2, TP53 or CHEK2 mutation, we demonstrated that sequencing the matching tumor can help reclassify germline VUS based on second events hitting the same gene and provide clinically relevant information. We then explored the concept of oligogenic inheritance of familial breast cancer, and obtained data suggestive of the pertinence of this model. Analyzing the combined segregation patterns of low-frequency variants in affected familial relatives of 54 of our index patients, we found significantly higher segregation rates of rare variants in cancer-related genes in families in which affected members share a similar breast cancer phenotype, as compared to phenotypically heterogeneous families. Furthermore, cancer genes with disease-cosegregating variants harbored second
(MED - Sciences médicales) -- UCL, 2019