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Figure S2. Microscopic finding of a carcinoma of neuroendocrine cells in the liver biopsy from case two, the original image of Fig. 8 before adjustment in Photoshop to remove the pink background and increase the contrast. (PDF 3192 kb)

Figure S1. Microscopic finding of a carcinoma of neuroendocrine cells in the liver biopsy from case one, the original image of Fig. 5, before adjustment in Photoshop to remove the pink background and increase the contrast. (PDF 3304 kb)

Recent studies have revealed the mutational signatures underlying the somatic evolution of cancer, and the prevalences of associated somatic genetic variants. Here we estimate the intensity of positive selection that drives mutations to high frequency in tumors, yielding higher prevalences than expected on the basis of mutation and neutral drift alone. We apply this approach to a sample of 525 head and neck squamous cell carcinoma exomes, producing a rank-ordered list of gene variants by selection intensity. Our results illustrate the complementarity of calculating the intensity of selection on mutations along with tallying the prevalence of individual substitutions in cancer: while many of the most prevalently-altered genes were heavily selected, their relative importance to the cancer phenotype differs from their prevalence and from their P value, with some infrequent variants exhibiting evidence of strong positive selection. Furthermore, we extend our analysis of effect size by quantifying the degree to which mutational processes (such as APOBEC mutagenesis) contributes mutations that are highly selected, driving head and neck squamous cell carcinoma. We calculate the substitutions caused by APOBEC mutagenesis that make the greatest contribution to cancer phenotype among patients. Lastly, we demonstrate via in vitro biochemical experiments that the APOBEC3B protein can deaminate the cytosine bases at two sites whose mutant states are subject to high net realized selection intensities-PIK3CA E545K and E542K. By quantifying the effects of mutations, we deepen the molecular understanding of carcinogenesis in head and neck squamous cell carcinoma.

A major goal of cancer biology is determination of the relative importance of the genetic alterations that confer selective advantage to cancer cells. Tumor sequence surveys have frequently ranked the importance of substitutions to cancer growth by P value or a false-discovery conversion thereof. However, P values are thresholds for belief, not metrics of effect. Their frequent misuse as metrics of effect has often been vociferously decried, even in cases when the only attributable mistake was omission of effect sizes. Here, we propose an appropriate ranking—the cancer effect size, which is the selection intensity for somatic variants in cancer cell lineages. The selection intensity is a metric of the survival and reproductive advantage conferred by mutations in somatic tissue. Thus, they are of fundamental importance to oncology, and have immediate relevance to ongoing decision making in precision medicine tumor boards, to the selection and design of clinical trials, to the targeted development of pharmaceuticals, and to basic research prioritization. Within this commentary, we first discuss the scope of current methods that rank confidence in the overrepresentation of specific mutated genes in cancer genomes. Then we bring to bear recent advances that draw upon an understanding of the development of cancer as an evolutionary process to estimate the effect size of somatic variants leading to cancer. We demonstrate the estimation of the effect sizes of all recurrent single nucleotide variants in 22 cancer types, quantifying relative importance within and between driver genes.

The progression of cancer is an evolutionary process. During this process, evolving populations of cancer cells encounter restrictive ecological niches within the body, such as the primary tumor, the circulatory system, and diverse metastatic sites. Heterogeneous populations of cancer cells undergo selection for adaptive phenotypes, which shapes molecular genetic variation amid concomitant genetic drift. Cell lineages undergo convergent evolution toward phenotypes known as the hallmarks of cancer that promote cancer initiation, growth, and metastasis. Efforts to prevent or delay cancer evolution-and progression-require a deep understanding of the underlying molecular evolutionary processes. Herein we discuss a suite of concepts and tools from evolutionary and ecological theory that can inform-and possibly transform-cancer biology in new and meaningful ways. These concepts and tools include comparative research on cancer across diverse species and application of phylogenetic approaches to analyze the evolution of tumor progression and metastasis. Fitness landscapes can be leveraged to describe potential trajectories of cancer evolution, mapping positive selection and neutral evolution of proto-oncogenes, tumor suppressors, and other functional elements. We also highlight current challenges to applying these concepts and propose research areas that, by incorporating these concepts, could identify new therapeutic modes and vulnerabilities in cancer.

The progression of cancer is an evolutionary process. During this process, evolving populations of cancer cells encounter restrictive ecological niches within the body, such as the primary tumor, the circulatory system, and diverse metastatic sites. Heterogeneous populations of cancer cells undergo selection for adaptive phenotypes, which shapes molecular genetic variation amid concomitant genetic drift. Cell lineages undergo convergent evolution toward phenotypes known as the hallmarks of cancer that promote cancer initiation, growth, and metastasis. Efforts to prevent or delay cancer evolution-and progression-require a deep understanding of the underlying molecular evolutionary processes. Herein we discuss a suite of concepts and tools from evolutionary and ecological theory that can inform-and possibly transform-cancer biology in new and meaningful ways. These concepts and tools include comparative research on cancer across diverse species and application of phylogenetic approaches to analyze the evolution of tumor progression and metastasis. Fitness landscapes can be leveraged to describe potential trajectories of cancer evolution, mapping positive selection and neutral evolution of proto-oncogenes, tumor suppressors, and other functional elements. We also highlight current challenges to applying these concepts and propose research areas that, by incorporating these concepts, could identify new therapeutic modes and vulnerabilities in cancer.