Journal Article

Tumor sequencing is useful to refine the analysis of germline variants in unexplained high-risk breast cancer families

Merhi, Ahmad, Ambroise, Jérôme, Vikkula, Miikka, Canon, Jean-Luc, Bar, Isabelle, Vuylsteke, Peter, Machiels, Jean-Pascal, Limaye, Nisha, Helaers, Raphaël, De Leener, Anne, Berlière, Martine, Rothé, Françoise, Schoonjans, Céline A., Khoury, Elsa, Van Marcke, Cédric, Delrée, Paul, Brouillard, Pascal, Duhoux, François P., Galant, Christine

2020

Overview

Background Multigene panels are routinely used to assess for predisposing germline mutations in families at high breast cancer risk. The number of variants of unknown significance thereby identified increases with the number of sequenced genes. We aimed to determine whether tumor sequencing can help refine the analysis of germline variants based on second somatic genetic events in the same gene. Methods Whole-exome sequencing (WES) was performed on whole blood DNA from 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1 , BRCA2 , TP53 , or CHEK2 mutation. Rare variants were retained in a list of 735 genes. WES was performed on matched tumor DNA to identify somatic second hits (copy number alterations (CNAs) or mutations) in the same genes. Distinct methods (among which immunohistochemistry, mutational signatures, homologous recombination deficiency, and tumor mutation burden analyses) were used to further study the role of the variants in tumor development, as appropriate. Results Sixty-eight patients (97%) carried at least one germline variant (4.7 ± 2.0 variants per patient). Of the 329 variants, 55 (17%) presented a second hit in paired tumor tissue. Of these, 53 were CNAs, resulting in tumor enrichment (28 variants) or depletion (25 variants) of the germline variant. Eleven patients received variant disclosure, with clinical measures for five of them. Seven variants in breast cancer-predisposing genes were considered not implicated in oncogenesis. One patient presented significant tumor enrichment of a germline variant in the oncogene ERBB2 , in vitro expression of which caused downstream signaling pathway activation. Conclusion Tumor sequencing is a powerful approach to refine variant interpretation in cancer-predisposing genes in high-risk breast cancer patients. In this series, the strategy provided clinically relevant information for 11 out of 70 patients (16%), adapted to the considered gene and the familial clinical phenotype.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Algorithms / Bioinformatics / Biomedical and Life Sciences / Biomedicine / BRCA1 protein / BRCA2 protein / Breast cancer / Cancer Research / Copy number / Deoxyribonucleic acid / DNA / DNA sequencing / ErbB-2 protein / Gene mutation / Genes / Genetic aspects / Genetic counseling / Genetic screening / Genetic testing / Genomes / Germline / Haplotypes / Health aspects / Homologous recombination / Immunohistochemistry / Kinases / Mutation / Mutational signatures / Oncology / Ovarian cancer / p53 Protein / Patients / Phenotypes / Predisposition / Research Article / Risk factors / Second hit / Signal transduction / Surgical Oncology / Tumor proteins / Tumorigenesis / Variant of unknown significance