Figure 1.

Detection of CHIP-associated alterations in comprehensive genomic profiling of solid tumor specimens. (A) In hybrid-capture, high-depth DNA sequencing, variants may arise from unfiltered germ line mutations present in all cells (blue dots), somatic mutations present in cancer cells (gold and green dots), and potentially somatic mutations present in nontumor cells (orange dots). If a somatic mutation is present in all cancer cells, then its expected VAF depends on tumor purity (ie, the percentage of tumor cells relative to all cells) and the chromosomal ploidy at its genomic locus. When the observed VAF of a mutation is significantly different from the frequency expected from tumor purity, it may only be present in a subpopulation of cancer cells or exist in nontumor elements. The VAFs in this sketch are calculated assuming a diploid genome in both tumor and nontumor cells. (B) The log odds ratio for rate of detecting genomic alterations in patients >60 years relative to those <60 years for 257 genes in each tumor type was calculated. Each data point on the boxplot represents the log odds for a single tumor type in a single gene. Genes presented have an adjusted P value of <1 by t test after Bonferroni correction for multiple hypothesis testing (*P < .05). (C) Logistic regression of rate of detection, by percentage of patients, for genomic alterations in DNMT3A, TET2, SF3B1, and ASXL1 as a function of patient age for all solid tumor samples. (D) VAF for genomic alterations in DNMT3A, TET2, SF3B1, and ASXL1 by age group (*P < .05, **P < 1e-05, and ***P < 1e-10, respectively as calculated by the Kruskal-Wallis test corrected with the Dunn test for multiple comparisons). Logistic regression of VAFs by age corroborates these results (supplemental Figure 5). (E) Logistic regression of the rate of detection versus tumor purity (DNMT3A, P < 2.0e-16; TET2, P < 2.0e-16; ASXL, P < 1.0e-06; and SF3B1, P < 1.9e-07).