Effect Sizes of Somatic Mutations in Cancer

Abstract

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.

Figure 1.

Deconvolution of prevalence by mutation rates to yield selection intensity for recurrent amino acid mutations within three oncoproteins caused by single-nucleotide changes in lung adenocarcinoma. A) Observed substitution rates—after correction under an assumption of complete intragenic epistasis—are divided by (B) the expected substitution rates in the absence of selection. Expected substitution rates in the absence of selection are calculated as (C) the average per-site synonymous mutation rate of the gene, normalized for (D) the average weight of trinucleotide mutational signature burden for that tissue. The quotient of observed to expected numbers of substitutions is (E) the selection intensity, or cancer effect size, of variants.

Figure 2.

The 25 single-nucleotide variants (red = dndscv Q < 0.05; black = dndscv Q ≥ 0.05) with the highest selection intensity from (A) 675 LUAD tumors and (B) 600 LUSC tumors, within the expertly curated COSMIC list of drivers (39), ranked by selection intensity (bar, uniquely colored by gene identity, to the right of variant name), determined by deconvolving prevalence (number to the left of the variant name), by mutation rate (bar, uniquely colored by gene identity, to the left of prevalence, and rate × 10^–6, to the left of the bar). The asterisk corresponds to a nonsense mutation. LUAD = lung adenocarcinoma; LUSC = lung squamous cell carcinoma.

Figure 3.

Cancer effect sizes of recurrent somatic substitutions in six of the 22 cancer types analyzed. Effect sizes greater than 1 × 10^3.5 are indicated by ticks along the tumor-type axes. The highest 50 effect sizes are labeled within each tumor. Names of genes that have more than one mutation listed within or between tumors are uniquely colored. Genes deemed statistically significantly overburdened with nonsynonymous mutation (2) are depicted by a red circle next to variant names, and the prevalence of each substitution is represented by the size of this circle. NC refers to a non-coding single-nucleotide variant outside an exon (eg, 5’ or 3’ UTRs). 108 LUAD, 108 LUSC, and 28 SKCM tumors from the Yale-Gilead collaboration are included in the plot. LGG = brain lower grade glioma; SKCM = skin cutaneous melanoma (primary); READ = rectum adenocarcinoma; PRAD = prostate adenocarcinoma; LUAD = lung adenocarcinoma; LUSC = lung squamous cell carcinoma.