Cost-effective Whole Genome Sequencing Method Identifies Clinically Relevant Germline Variants in Patients Recruited in A Breast Cancer Clinic

Whole genome sequencing (WGS) is increasingly used to capture all possible biologically and clinically relevant germline variants in the human genome from cancer patients. However, the cost, large size, and complexity of this data presents a major challenge when considering implementing WGS technology as part of routine care. To assess the efficacy of integrating WGS in oncological settings, we have investigated WGS data from the germline of at least 100 breast cancer (BC) patients recruited at a local clinic.

Consenting participants with a history of invasive BC that were recruited at a Montreal Canada hospital-based breast clinic provided blood samples for WGS and completed questionnaires. Clinical metrics were collected from medical charts. DNA was sequenced at the McGill Genome Centre using the cost effective Complete Genomics DNBSEQ-T7 technology. Data was processed using Digital Research Alliance of Canada’s high performance computing clusters and the Canadian Centre for Computational Genomics pipelines. Clinically relevant variants harboured by 11 known carriers were investigated, followed by the investigation of variants in 19 clinically actionable BC susceptibility genes (BCSG) according to NCCN guidelines, using ClinVar. Genetic data was aggregated with personal clinical data and family history.

In all, 74% of participants were prioritized for analysis and have completed sequencing. WGS data available from 98 participants exhibited high quality. All SNP/INDEL pathogenic variants were validated in the 11 known carriers. The investigation of 19 BCSG’s identified 6 pathogenic/likely pathogenic variants in participants not previously known to be carriers based on clinical reports. A review of clinical data provided information concerning lack of a priori BCSG testing for some cases.

Results indicate that WGS can detect variants from prior genetic screens and identify new carriers of actionable variants that for whatever reason where not known to be carriers.

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