Cancer is driven by somatic and germline variants in oncogenes and tumour suppressor genes. Genes containing germline variants that increase cancer risk are called cancer predisposition genes. It is important to determine if a variant in a cancer predisposition gene is of germline origin as this directly factors into the clinical care of cancer patients and their relatives who share these variants.
As part of The Advanced Genomics Collaboration between the University of Melbourne and Illumina, we routinely identify germline variants in cancer predisposition genes through matched tumour-normal whole genome sequencing. Variants are prioritised for manual curation using automated variant classification tools which are based on international guidelines for interpreting variant pathogenicity. Pathogenic and likely pathogenic variants in cancer predisposition genes are then identified and reported to assist clinicians with patient management.
We have reported germline variants in 15.4% of 513 patients and identified three non-mutually exclusive categories. First, variants may have therapeutic implications if they are biomarkers for response to therapeutic agents. Second, variants may be detected in cancer predisposition genes that are not associated with predisposition to the patient’s cancer type. These incidental germline findings may have clinical implications for patients and their families. Lastly, integrating molecular information from tumour whole genome and transcriptome sequencing, alongside histopathology review, informs the interpretation of germline variants of uncertain significance. In some cases, this prompts their reporting for further clinical interpretation and investigation.
Case studies illustrating these categories will be presented to highlight how germline curation informs treatment strategies, surveillance, and risk management of cancer patients.