Cancer Evolution Is Associated with Pervasive Positive Selection on Globally Expressed Genes

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.Author Summary: Cancer is a short-term evolutionary process that occurs within our bodies. Here, we demonstrate that the cancer evolutionary process differs greatly from other evolutionary processes. Most evolutionary processes are dominated by purifying selection (that removes harmful mutations). In contrast, in cancer evolution the dominance of purifying selection is much reduced, allowing for an easier detection of the signals of positive selection (that increases the likelihood beneficial mutations will persist). Mutations affected by positive selection within tumors are particularly interesting, as these are the mutations that allow cancer cells to acquire new capabilities important for transformation, tumor maintenance, drug resistance and metastasis. We demonstrate that, within tumors, positive selection strongly affects somatic mutations occurring within genes that are expressed globally, across all human tissues. Fitting with this, we show that genes that are already known to be involved in cancer tend to more often be globally expressed across tissues. However, even when such known cancer genes are removed from consideration, there is significantly more positive selection on the remaining globally expressed genes, suggesting that they are enriched for yet undiscovered cancer related functions. The results we present are important both for understanding cancer as an evolutionary process and to the continuing quest to identify new genes and pathways contributing to cancer.