Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation.
Patterns of gene expression in tumors can arise as a consequence of or result in genomic instability, characterized by the accumulation of somatic copy number alterations (SCNAs) and point mutations (PMs). Expression signatures have been widely used as markers for genomic instability, and both SCNAs and PMs could be thought to associate with distinct signatures given their different formation mechanisms. Here we test this notion by systematically investigating SCNA, PM, and transcriptome data from 2660 cancer patients representing 11 tumor types. Notably, our data indicate that similar expression signatures can be derived from correlating gene expression with either SCNA or PM load. Gene sets related to cell growth and proliferation generally associated positively, and immunoregulatory gene sets negatively, with variant burden. In-depth analyses revealed several genes whose de-regulation correlates with SCNA but not with PM burden, yielding downstream effectors ofTP53andMYCsignaling unique to high-SCNA tumors. We compared our findings to expression changes observed in two different cancer mouse models with persistent mitotic chromosomal instability, observing a decrease in proliferative expression signatures. Our results suggest that overexpression of cell-cycle-related genes are a characteristic of proliferation, and likely tumor evolution, rather than ongoing genomic instability.
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg 69117, Germany.
Christopher
C
Buccitelli
Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg 69120, Germany.
Lorena
L
Salgueiro
Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg 69120, Germany.
Konstantina
K
Rowald
Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg 69120, Germany.
Rocio
0000-0002-0855-7917
R
Sotillo
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg 69117, Germany.
Balca R
0000-0002-3903-9354
BR
Mardin
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg 69117, Germany.|EMBL-European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, United Kingdom.
Jan O
0000-0002-2798-3794
JO
Korbel
D000782:Aneuploidy; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D056915:DNA Copy Number Variations; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D000067552:Mutation Accumulation; D009369:Neoplasms / Q000235:genetics*; D017354:Point Mutation; D059467:Transcriptome
D018797:Cell Cycle Proteins