Diverse structural variants cluster near breakage-fusion-bridge site in cancer genomes

Abstract DNA rearrangements creating structural variants (SVs) are common features of all cancers, especially solid tumors. SVs can lead to cancer gene activation and inactivation, influencing carcinogenesis, immune escape, and tumor evolution. Due to the diverse mechanisms, they are highly challenging to identify accurately using short-read sequencing. To address this, we size-selected DNA to be greater than 15 kb and sequenced DNA to 20–30x coverage from cell lines representing three solid tumor types. Using Severus, a suite of tools optimized for somatic alterations in tumor-only sequences, we identified insertions, deletions, duplications, and inversions from 50 bp to over 218 Mb. We also characterized specialized inversions such as foldback inversions, a hallmark of breakage-fusion-bridge (BFB) events; reciprocal translocations; and chromosome-level gain, loss, and loss-of-heterozygosity events. Our approach permits comprehensive analysis of all the major classes of DNA mutation and rearrangements while providing a more comprehensive profile of genetic alterations in cancer. The loss of a telomere can lead to BFB events, causing local gene amplification and rearrangement and are the major cause of amplification of oncogenes such as ERBB2/HER2 and YAP1. BFB can be associated with chromothripsis or other complex rearrangements. In the 20 Mb surrounding BFB events we find a highly significant clustering of other SVs, including templated insertions, inversion-translocations, and complex inversions in breast, cervical, and pancreatic tumors. Therefore, BFB events initiate a complex process of rearrangement following loss of a telomere and contribute to tumor formation and progression. Biography Michael Dean is a senior investigator in the Laboratory of Translational Genomics. He obtained his PhD from the Biochemistry Department at the Boston University School of Medicine. He performed his postdoctoral studies at the National Cancer Institute, Center for Cancer Research (CCR), on the MET oncogene and cystic fibrosis gene. He is a member of the American Society of Human Genetics, the American Association of Cancer Research, and the Human Genome Organization (HUGO), and is an adjunct faculty member at Hood College. In 2022, Dr. Dean received the Hubert H. Humphrey Award for Service to America.