Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes.

Abstract

Advanced and metastatic tumors with complex treatment histories drive cancer mortality. Here we describe the POG570 cohort, a comprehensive whole-genome, transcriptome and clinical dataset, amenable for exploration of the impacts of therapies on genomic landscapes. Previous exposure to DNA-damaging chemotherapies and mutations affecting DNA repair genes, including POLQ and genes encoding Polζ, were associated with genome-wide, therapy-induced mutagenesis. Exposure to platinum therapies coincided with signatures SBS31 and DSB5 and, when combined with DNA synthesis inhibitors, signature SBS17b. Alterations in ESR1, EGFR, CTNNB1, FGFR1, VEGFA and DPYD were consistent with drug resistance and sensitivity. Recurrent noncoding events were found in regulatory region hotspots of genes including TERT, PLEKHS1, AP2A1 and ADGRG6. Mutation burden and immune signatures corresponded with overall survival and response to immunotherapy. Our data offer a rich resource for investigation of advanced cancers and interpretation of whole-genome and transcriptome sequencing in the context of a cancer clinic.

• Authors: Erin Pleasance, Emma Titmuss, Laura Williamson, Harwood Kwan, Luka Culibrk, Eric Y Zhao, Katherine Dixon, Kevin Fan, Reanne Bowlby, Martin R Jones, Yaoqing Shen, Jasleen K Grewal, Jahanshah Ashkani, Kathleen Wee, Cameron J Grisdale, My Linh Thibodeau, Zoltan Bozoky, Hillary Pearson, Elisa Majounie, Tariq Vira, Reva Shenwai, Karen L Mungall, Eric Chuah, Anna Davies, Mya Warren, Caralyn Reisle, Melika Bonakdar, Gregory A Taylor, Veronika Csizmok, Simon K Chan, Zusheng Zong, Steve Bilobram, Amir Muhammadzadeh, Darryl D'Souza, Richard D Corbett, Daniel MacMillan, Marcus Carreira, Caleb Choo, Dustin Bleile, Sara Sadeghi, Wei Zhang, Tina Wong, Dean Cheng, Scott D Brown, Robert A Holt, Richard A Moore, Andrew J Mungall, Yongjun Zhao, Jessica Nelson, Alexandra Fok, Yussanne Ma, Michael K C Lee, Jean-Michel Lavoie, Shehara Mendis, Joanna M Karasinska, Balvir Deol, Ana Fisic, David F Schaeffer, Stephen Yip, Kasmintan Schrader, Dean A Regier, Deirdre Weymann, Stephen Chia, Karen Gelmon, Anna Tinker, Sophie Sun, Howard Lim, Daniel J Renouf, Janessa Laskin, Steven J M Jones, Marco A Marra
• Journal: Nature cancer (Nat Cancer) Vol. 1 Issue 4 Pg. 452-468 (04 2020) ISSN: 2662-1347 [Electronic] England
• PMID: 35121966 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020. The Author(s), under exclusive licence to Springer Nature America, Inc.

Topics

• Humans
• Neoplasms (drug therapy)