NCM 2022: Clinical and functional significance of germline variation in cancer susceptibility and disease

Germline variants in cancer susceptibility genes contribute to 10–12% of all cancers. To date, we have performed nanopore genome sequencing for more than 100 individuals with a known or suspected susceptibility to cancer. Nanopore sequencing was sensitive to simple, complex, and epigenetic variants in well-characterized cancer predisposition genes. Long reads defined haplotypes associated with founder variants and revealed unforeseen allelic heterogeneity at the loci of recurrent deletions. Duplications identified by panel-based sequencing were found to occur frequently in tandem; informed by tumour pathology, indicating a duplication of uncertain significance as a strong candidate cause of disease. In research samples obtained from a case series of familial tumours, integrating long-read germline genome sequencing and short-read tumour genome and RNA sequencing implicated specific cancer pathways in disease. Together, our research findings suggest that long-read sequencing may provide insights into the natural history, functional consequence, and clinical significance of disease-causing genetic variation.