Abstract 4334: Linked read whole genome sequencing reveals pervasive chromosomal level instability and novel rearrangements in brain metastases from colorectal cancer

Little is known about the genomic features of brain metastases from colorectal cancer (CRC) and the contributing genetic factors. We conducted an analysis of large-scale structural aberrations, including chromosome aneuploidies, with a method called linked-read whole genome sequencing and a new somatic rearrangement detection software tool (ZoomX) to better understand the genomic architecture of brain metastases from CRC. We resolved on average 145 distal inter- and intra-chromosomal somatic junctions per sample with their exact haplotype information and basepair level breakpoints. In addition, we used a new haplotyping method based on these imbalances to generate cancer chromosome haplotypes of up to 146 Mbp long. We identified extensive chromosomal-level instability (CIN) in these cancer genomes, with an average of 90 large-scale copy number aberrations per sample in sizes ranging from hundreds of Kbp to hundreds of Mbp. A substantial fraction of CIN is likely attributable to earlier chromothripsis events. For example, we identified multiple chromothripsis events disrupting the loci of known cancer genes such as TP53, an essential colon cancer driver. We identified novel rearrangements including an oncogenic gene fusion; e.g. SET/DPP10 among these metastatic samples. A majority of chromosome arms demonstrated an allelic imbalance across all of the samples. In summary, the analysis revealed pervasive chromosome-level genome instability as a potential contributor to devastating brain invasion by CRC. It also demonstrated the advantages of linked-read whole genome sequencing. This approach is cost-effective and represents a high-resolution tool to assess genome-wide rearrangements and to generate megabase-scale haplotypes. Citation Format: Li C. Xia, John M. Bell, Christina Wood-Bouwens, Daniel A. King, GiWon Shin, Stephanie Greer, Ian D. Connolly, Melanie H. Gephart, Hanlee P. Ji. Linked read whole genome sequencing reveals pervasive chromosomal level instability and novel rearrangements in brain metastases from colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4334.