Mosaic mutations in blood DNA sequence are associated with solid tumor cancers

Abstract

Recent understanding of the causal role of blood-detectable somatic protein-truncating DNA variants in leukemia prompts questions about the generalizability of such observations across cancer types. We used the cancer genome atlas exome sequencing (~8000 samples) to compare 22 different cancer phenotypes with more than 6000 controls using a case-control study design and demonstrate that mosaic protein truncating variants in these genes are also associated with solid-tumor cancers. The absence of these cancer-associated mosaic variants from the tumors themselves suggest these are not themselves tumor drivers. Through analysis of different cancer phenotypes we observe gene-specificity for mosaic mutations. We confirm a specific link between PPM1D and ovarian cancer, consistent with previous reports linking PPM1D to breast and ovarian cancer. Additionally, glioblastoma, melanoma and lung cancers show gene specific burdens of mosaic protein truncating mutations. Taken together, these results extend existing observations and broadly link solid-tumor cancers to somatic blood DNA changes.

Fig. 1

Blood vs. tumor allele balance for each sample with mosaic PTV in a PPM1D, b TET2, c DNMT3A, d ASXL1. Observed in blood mosaic mutations are strongly depleted from the tumor somatic DNA (Wilcoxon test p < 10⁻¹⁶)

Fig. 2

Solid-tumor cancer phenotypes show gene specificity with respect to mosaic PTVs. a Empirical enrichment of the different cancer phenotypes with mosaic PTVs b Per gene significance of mosaic PTV burden in each cancer phenotype. Experiment-wise significance level is set with Bonferroni correction for multiple phenotypes tested. Ovarian cancer shows previously reported specific association to PPM1D mosaic PTVs