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.
Highlights
Several recent studies[1, 2] have reported associations of mosaic protein truncating variants (PTV) in PPM1D, TET2, ASXL1, and DNMT3A with blood cancers
We sought to more fully explore the relationship of these somatic mutations, clearly causally linked to blood cancers, in solid tumor cancer using a large assembly of germline and somatic exome DNA sequences of 7979 cancer cases from the cancer genome atlas (TCGA)[4] and performed a large-scale case–control study with 6177 population controls with no cancer phenotype reported
Our study investigates the association of the mosaic proteintruncating variants in four genes previously associated with blood cancer risk in blood samples from patients with solid-tumor diagnoses
Summary
Several recent studies[1, 2] have reported associations of mosaic protein truncating variants (PTV) in PPM1D, TET2, ASXL1, and DNMT3A with blood cancers. Such mosaic mutations in PPM1D have been convincingly associated with breast and ovarian cancer3—since these mutations are somatic, rather than germline, their role in causation has not been clear. We sought to more fully explore the relationship of these somatic mutations, clearly causally linked to blood cancers, in solid tumor cancer using a large assembly of germline and somatic exome DNA sequences of 7979 cancer cases from the cancer genome atlas (TCGA)[4] and performed a large-scale case–control study with 6177 population controls with no cancer phenotype reported
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