The Somatic Nature of Cancer Allows It to Affect Highly Constrained Genes.

Cancer is special among genetic disorders in two major ways: first, cancer is a disease of the most basic of cellular functions, such as cell proliferation, differentiation, and the maintenance of genomic integrity. Second, in contrast to most genetic disorders that are mediated by germline (hereditary) mutations, cancer is largely a somatic disease. Here we show that these two traits are not detached and that it is the somatic nature of cancer that allows it to affect the most basic of cellular functions. We begin by demonstrating that cancer genes are both more functionally central (as measured by their patterns of expression and protein interaction) and more evolutionarily constrained than non-cancer genetic disease genes. We then compare genes that are only modified somatically in cancer (hereinafter referred to as "somatic cancer genes") to those that can also be modified in a hereditary manner, contributing to cancer development (hereinafter referred to as "hereditary cancer genes"). We show that both somatic and hereditary cancer genes are much more functionally central than genes contributing to non-cancer genetic disorders. At the same time, hereditary cancer genes are only as constrained as non-cancer hereditary disease genes, while somatic cancer genes tend to be much more constrained in evolution. Thus, it appears that it is the somatic nature of cancer that allows it to modify the most constrained genes and, therefore, affect the most basic of cellular functions.

Variation in KRAS driver substitution distributions between tumor types is determined by both mutation and natural selection.

Different tumor types vary greatly in their distribution of driver substitutions. Here, we analyzed how mutation and natural selection contribute to differences in the distribution of KRAS driver substitutions between lung, colon and pancreatic adenocarcinomas. We were able to demonstrate that both differences in mutation and differences in selection drive variation in the distribution of KRAS driver substitutions between tumor types. By accounting for the effects of mutation on the distribution of KRAS driver substitutions, we could identify specific KRAS driver substitutions that are more favored by selection in specific tumor types. Such driver substitutions likely improve fitness most when they occur within the context of the tumor type in which they are preferentially favored. Fitting with this, we found that driver substitutions that are more favored by natural selection in a specific type of tumor tend to associate with worse clinical outcomes specifically in that type of tumor.

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.