Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics

Ekta Khurana, et al., Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics, Science 342, 2013

We used patterns of polymorphisms in functionally annotated regions in 1092 humans to identify deleterious variants; then we experimentally validated candidates. We analyzed both coding and noncoding regions, with the former corroborating the latter. We found regions particularly sensitive to mutations (“ultrasensitive”) and variants that are disruptive because of mechanistic effects on transcription-factor bind site (that is, “motif-breakers”).

We developed a computational tool (FunSeq), those application to ~90 cancer genomes reveals nearly a hundred candidate noncoding drivers.

Because somatic variants from diverse tumors exhibit different sets of properties, we analyzed variants from a wide range of cancer types: prostate, breast, and medulloblastoma. We found that ~99% of somatic SNVs occur in noncoding regions, including TFBSs, ncRNAs, and pseudogenes.

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