Abstract P5-03-04: Co-segregation of rare possibly-damaging variants in cancer-related genes correlates with phenotypic homogeneity in familial breast cancer
Authors: Van Marcke Cedric , Helaers Raphaël , Schoonjans Céline A , Ambroise Jérôme , Berlière Martine , Canon Jean-Luc , Vuylsteke Peter , Machiels Jean-Pascal , Vikkula Miikka , Duhoux Francois P 
Published: March 2020

BACKGROUND Breast cancer (BC) is a complex disease. While Mendelian mutations in high-penetrance genes predispose to some familial forms, others are due to multiple common low-penetrance polymorphisms. However, it is unclear if the combination of some rare coding variants has an effect. As some Mendelian forms demonstrate genotype-phenotype correlations, we hypothesized co-segregation of rare variants in cancer-related genes would be more frequent in high-risk families with a uniform BC phenotype among relatives. METHODS Whole-exome sequencing was performed on germline DNA from unrelated BC patients referred for genetic testing but without a causative mutation and for which DNA was available from at least one second relative with BC. We retained rare (&lt; 1.5% in ExaC) in silico possibly damaging variants (splice alteration, nonsense or frameshift mutation, or missense variant considered deleterious by at least 2 different algorithms) in a list of 735 cancer or DNA repair related genes. We assessed correlation between segregation of these variants in affected relatives (studied by Sanger sequencing) and tumor phenotypes. A familial uniform BC phenotype was denoted as sharing the same BC histology and the same clinical molecular classification, based on the expression of the hormone receptors and HER2. RESULTS Of the 54 families, 23 (43%) presented a uniform phenotype across the affected relatives. We identified 251 variants. The mean number of variants tested did not differ between families with a similar BC phenotype and families with different BC phenotypes (4.3 vs 4.9 respectively, two-sided T-test p=0.19). The proportion of disease co-segregating variants inside each family was however significantly higher in families with a uniform BC phenotype than in families with a heterogeneous BC phenotype (57.8% vs 30.2%, p&lt;0.01 adjusted for the number of relatives and meioses within each family). Sequencing of matched tumor DNA, obtained for 44 probands, revealed co-segregating variants were more frequently enriched by a somatic event (18.6 vs 4.5%, Mann-Whitney test p=0.042 and 8.3 vs 1.1%, p=0.031 for the families with a uniform or a heterogeneous breast cancer phenotype, respectively). CONCLUSION In this cohort of families at high risk of BC, the proportion of co-segregating variants was significantly higher in the families in which the affected relatives shared a uniform BC phenotype. Investigation of oligogenic models could be more pertinent in this subgroup of families. The theory of bi-allelic gene inactivation required to drive cancer, shown for several Mendelian genes, could also be pertinent in the oligogenic model of inheritance. This study should be replicated in an independent cohort for confirmation.

Citation Format: Cedric Van Marcke, Raphaël Helaers, Céline A Schoonjans, Jérôme Ambroise, Martine Berlière, Jean-Luc Canon, Peter Vuylsteke, Jean-Pascal Machiels, Miikka Vikkula, Francois P Duhoux. Co-segregation of rare possibly-damaging variants in cancer-related genes correlates with phenotypic homogeneity in familial breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-04.