Strength of selection in lung tumors correlates with clinical features better than tumor mutation burden

Abstract

Single nucleotide substitutions are the most common type of somatic mutations in cancer genome. The goal of this study was to use publicly available somatic mutation data to quantify negative and positive selection in individual lung tumors and test how strength of directional and absolute selection is associated with clinical features. The analysis found a significant variation in strength of selection (both negative and positive) among tumors, with median selection tending to be negative even though tumors with strong positive selection also exist. Strength of selection estimated as the density of missense mutations relative to the density of silent mutations showed only a weak correlation with tumor mutation burden. In the "all histology together" analysis we found that absolute strength of selection was strongly correlated with all clinically relevant features analyzed. In histology-stratified analysis selection was strongest in small cell lung cancer. Selection in adenocarcinoma was somewhat higher compared to squamous cell carcinoma. The study suggests that somatic mutation- based quantifying of directional and absolute selection in individual tumors can be a useful biomarker of tumor aggressiveness.

Figure 1

The distribution of the log ratio of the density of missense to the density of silent mutations. The vertical red line marks the relative density expected when the global selection is zero, that is, the density of missense mutations equals the density of silent mutations. The median log ratio is shown as a vertical line on the box plot. The standard deviation SD = 0.268 is shown as a horizontal box. Vertical bars show the 95% confidence interval.

Figure 2

Upper panel shows stratification of tumors into five categories of strength of directional selection. Vertical red line marks the point of zero global selection. The middle and low rows show distributions of values of clinically relevant features in tumors categorized by strength of the directional selection. Note U-shaped or reverse U-shaped associations with the clinically relevant features.

Figure 3

The distribution of the ratio of the density of missense to the density of silent mutations in adenocarcinoma (top panel), squamous cell carcinoma (middle panel), and small cell lung cancer (lower panel). The vertical red line marks the relative density expected in the absence of selection. Median log ratio is shown as the vertical line on the box plot.