Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes
Authors:
- 13 April 2020
- journal article
- research article
- Published by Springer Nature in Nature Cancer
- Vol. 1 (4) , 452-468
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.Keywords
Funding Information
- Genome Canada (202SEQ, 212SEQ)
- Genome British Columbia (12002)
- Canada Foundation for Innovation (20070, 30981, 33408)
- Canada Genomics Enterprise (35444)
- Genome Canada (212SEQ)
This publication has 109 references indexed in Scilit:
- Signatures of mutational processes in human cancerNature, 2013
- DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegiseLife, 2013
- Deciphering Signatures of Mutational Processes Operative in Human CancerCell Reports, 2013
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Comprehensive molecular portraits of human breast tumoursNature, 2012
- DELLY: structural variant discovery by integrated paired-end and split-read analysisBioinformatics, 2012
- Strelka: accurate somatic small-variant calling from sequenced tumor–normal sample pairsBioinformatics, 2012
- Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing dataBioinformatics, 2011
- ChimeraScan: a tool for identifying chimeric transcription in sequencing dataBioinformatics, 2011
- A small-cell lung cancer genome with complex signatures of tobacco exposureNature, 2009