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- Title
Exome-wide analysis of bi-allelic alterations identifies a Lynch phenotype in The Cancer Genome Atlas.
- Authors
Buckley, Alexandra R.; Ideker, Trey; Carter, Hannah; Harismendy, Olivier; Schork, Nicholas J.
- Abstract
Background: Cancer susceptibility germline variants generally require somatic alteration of the remaining allele to drive oncogenesis and, in some cases, tumor mutational profiles. Whether combined germline and somatic bi-allelic alterations are universally required for germline variation to influence tumor mutational profile is unclear. Here, we performed an exome-wide analysis of the frequency and functional effect of bi-allelic alterations in The Cancer Genome Atlas (TCGA). Methods: We integrated germline variant, somatic mutation, somatic methylation, and somatic copy number loss data from 7790 individuals from TCGA to identify germline and somatic bi-allelic alterations in all coding genes. We used linear models to test for association between mono- and bi-allelic alterations and somatic microsatellite instability (MSI) and somatic mutational signatures. Results: We discovered significant enrichment of bi-allelic alterations in mismatch repair (MMR) genes and identified six bi-allelic carriers with elevated MSI, consistent with Lynch syndrome. In contrast, we find little evidence of an effect of mono-allelic germline variation on MSI. Using MSI burden and bi-allelic alteration status, we reclassify two variants of unknown significance in MSH6 as potentially pathogenic for Lynch syndrome. Extending our analysis of MSI to a set of 127 DNA damage repair (DDR) genes, we identified a novel association between methylation of SHPRH and MSI burden. Conclusions: We find that bi-allelic alterations are infrequent in TCGA but most frequently occur in BRCA1/2 and MMR genes. Our results support the idea that bi-allelic alteration is required for germline variation to influence tumor mutational profile. Overall, we demonstrate that integrating germline, somatic, and epigenetic alterations provides new understanding of somatic mutational profiles.
- Subjects
CANCER genes; MICROSATELLITE repeats; SOMATIC cells; METHYLATION; EPIGENETICS
- Publication
Genome Medicine, 2018, Vol 10, Issue 1, pN.PAG
- ISSN
1756-994X
- Publication type
Article
- DOI
10.1186/s13073-018-0579-5