Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes.
Erin PleasanceEmma TitmussLaura WilliamsonHarwood KwanLuka CulibrkEric Y ZhaoKatherine DixonKevin FanReanne BowlbyMartin R JonesYaoqing ShenJasleen K GrewalJahanshah AshkaniKathleen WeeCameron J GrisdaleMy Linh ThibodeauZoltan BozokyHillary PearsonElisa MajounieTariq ViraReva ShenwaiKaren L MungallEric ChuahAnna DaviesMya WarrenCaralyn ReisleMelika BonakdarGregory A TaylorVeronika CsizmokSimon K ChanZusheng ZongSteve BilobramAmir MuhammadzadehDarryl D'SouzaRichard D CorbettDaniel MacMillanMarcus CarreiraCaleb ChooDustin BleileSara SadeghiWei ZhangTina WongDean ChengScott D BrownRobert A HoltRichard A MooreAndrew J MungallYongjun ZhaoJessica NelsonAlexandra FokYussanne MaMichael K C LeeJean-Michel LavoieShehara MendisJoanna M KarasinskaBalvir DeolAna FisicDavid F SchaefferStephen YipKasmintan SchraderDeirdre WeymannDeirdre WeymannStephen ChiaKaren GelmonAnna TinkerSophie SunHoward LimDaniel J RenoufJanessa LaskinSteven J M JonesMarco A MarraPublished in: Nature cancer (2020)
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 PolĪ¶, 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.
Keyphrases
- genome wide
- copy number
- dna methylation
- papillary thyroid
- dna repair
- small cell lung cancer
- squamous cell
- gene expression
- single cell
- dna damage
- primary care
- circulating tumor
- transcription factor
- rna seq
- cell free
- type diabetes
- cardiovascular disease
- tyrosine kinase
- high glucose
- genome wide identification
- young adults
- risk factors
- bioinformatics analysis
- cardiovascular events
- big data
- deep learning
- endothelial cells
- data analysis
- genome wide analysis