title: Cancer evolution is associated with pervasive positive selection on globally expressed genes.
abstract: Cancer is an evolutionary process in which cells acquire new transformative, proliferative and metastatic capabilities. A full understanding of cancer requires learning the dynamics of the cancer evolutionary process. We present here a large-scale analysis of the dynamics of this evolutionary process within tumors, with a focus on breast cancer. We show that the cancer evolutionary process differs greatly from organismal (germline) evolution. Organismal evolution is dominated by purifying selection (that removes mutations that are harmful to fitness). In contrast, in the cancer evolutionary process the dominance of purifying selection is much reduced, allowing for a much easier detection of the signals of positive selection (adaptation). We further show that, as a group, genes that are globally expressed across human tissues show a very strong signal of positive selection within tumors. Indeed, known cancer genes are enriched for global expression patterns. Yet, positive selection is prevalent even on globally expressed genes that have not yet been associated with cancer, suggesting that globally expressed genes are enriched for yet undiscovered cancer related functions. We find that the increased positive selection on globally expressed genes within tumors is not due to their expression in the tissue relevant to the cancer. Rather, such increased adaptation is likely due to globally expressed genes being enriched in important housekeeping and essential functions. Thus, our results suggest that tumor adaptation is most often mediated through somatic changes to those genes that are important for the most basic cellular functions. Together, our analysis reveals the uniqueness of the cancer evolutionary process and the particular importance of globally expressed genes in driving cancer initiation and progression.
authors.affiliation: Rachel & Menachem Mendelovitch Evolutionary Processes of Mutation & Natural Selection Research Laboratory, Department of Genetics, the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Sheli L
authors.initials: SL
authors.lastname: Ostrow
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Barshir
authors.affiliation: Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, Integrated Department of Immunology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: DeGregori
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Esti
authors.initials: E
authors.lastname: Yeger-Lotem
authors.affiliation: Rachel & Menachem Mendelovitch Evolutionary Processes of Mutation & Natural Selection Research Laboratory, Department of Genetics, the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Hershberg
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D012641:Selection, Genetic