Month: January 2016

Mutational Strand Asymmetries in Cancer Genomes

[PMID:26806129] [Cell]

Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair

“Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional (“T-class”) asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative (“R-class”) asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication.” Work from Gad Getz.

subRVIS

[PMID:26781712] [Genome Biology]

The intolerance to functional genetic variation of protein domains predicts the localization of pathogenic mutations within genes

“evaluate the intolerance of genic sub-regions using two biological sub-region classifications. We show that the intolerance scores of these sub-regions significantly correlate with reported pathogenic mutations. This observation extends the utility of intolerance scores to indicating where pathogenic mutations are mostly likely to fall within genes.”

Neutral Tumor Evolution

[PMID:26780609] [Nature Genetics]

Identification of neutral tumor evolution across cancer types

“the neutral power law fits with high precision 323 of 904 cancers from 14 types and from different cohorts. In malignancies identified as evolving neutrally, all clonal selection seemingly occurred before the onset of cancer growth and not in later-arising subclones, resulting in numerous passenger mutations that are responsible for intratumoral heterogeneity.”