Abstract
Despite significant advances in our understanding of genetic cancer susceptibility, known inherited cancer predisposition syndromes explain at most 20% of early-onset cancers. As early-onset cancer prevalence continues to increase, the need to assess previously inaccessible areas of the human genome, harnessing a trio or quad family-based architecture for variant filtration, may reveal further insights into cancer susceptibility. To assess a broader spectrum of variation than can be ascertained by multi-gene panel sequencing, or even whole genome sequencing with short reads, we employed long read whole genome sequencing using an Oxford Nanopore Technology (ONT) PromethION of 3 families containing an early-onset cancer proband using a trio or quad family architecture. Analysis included 2 early-onset colorectal cancer family trios and one quad consisting of two siblings with testicular cancer, all with unaffected parents. Structural variants (SVs), epigenetic profiles and single nucleotide variants (SNVs) were determined for each individual, and a filtering strategy was employed to refine and prioritize candidate variants based on the family architecture. The family architecture enabled us to focus on inapposite variants while filtering variants shared with the unaffected parents, significantly decreasing background variation that can hamper identification of potentially disease causing differences. Candidate de novo and compound heterozygous variants were identified in this way. Gene expression, in matched neoplastic and pre-neoplastic lesions, was assessed for one trio. Our study demonstrates the feasibility of a streamlined analysis of genomic variants from long read ONT whole genome sequencing and a way to prioritize key variants for further evaluation of pathogenicity, while revealing what may be missing from panel based analyses.
Competing Interest Statement
W.R.M. is a founder, shareholder and board member of Orion Genomics, which focuses on plant genomics. M.K. has received travel reimbursement for speaking at Oxford Nanopore Community Meetings. Spouse of M.K. is an Illumina Field Applications employee and is granted stock. Z.K.S. has intellectual property rights in SOPHiA Genetics and serves as an Associate Editor for JCO Precision Oncology and as a Section Editor for UpToDate. The immediate family member of Z.K.S. serves as a consultant in Ophthalmology for Adverum, Genentech, Neurogene, Novartis, Optos Plc, Outlook Therapeutics, and Regeneron outside the submitted work.