Comprehensive Study of Noncoding DNA Reveals Unexpectedly Few Cancer Drivers
Key findings
- The Pan-Cancer Analysis of Whole Genomes Consortium has analyzed cancer genome sequences from 2,658 patients across 38 types of cancer
- As part of that effort, researchers created rigorous new methods for detecting noncoding driver mutations, the DNA changes that "drive" cells down pathways toward cancer
- Despite the use of multiple methods of analysis, few novel noncoding driver point mutations were detected
- Interesting newly identified noncoding drivers did include 5'-end mutations in TP53, 3' untranslated region mutations in NFKBIZ and TOB1. Several previously reported noncoding elements seem to be transcription-associated mutations, not genuine drivers
- Although this study represents the largest collection of cancer whole genomes thus far, many more whole genomes will be needed to obtain sufficient statistical power to detect noncoding drivers
The Pan-Cancer Analysis of Whole Genomes Consortium (PCAWGC), a project of the International Cancer Genome Consortium and The Cancer Genome Atlas, has completed a mammoth undertaking of analyzing cancer whole genomes from 2,658 patients across 38 types of cancer. The core set of results was recently published in 22 articles in Nature and affiliated journals.
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Most large-scale genomic studies of cancer have focused on detecting driver mutations in protein-coding genes, but these represent <2% of the human genome. Ever since driver mutations were discovered in the noncoding TERT gene across multiple cancer types, it's been thought there may be numerous noncoding driver mutations in the "dark matter" of the genome.
As part of the PCAWGC effort, Esther Rheinbay, PhD, principal investigator at the Center for Cancer Research at Massachusetts General Hospital, Gad Getz, PhD, Paul C. Zamecnik chair in Oncology and director of Bioinformatics at the Mass General Cancer Center and Department of Pathology, created new methods of characterizing noncoding drivers. In Nature, they report finding some new candidates, but their main message is that the vast majority of cancer drivers occur in protein-coding regions.
Study Methods
For detecting driver point mutations (single-nucleotide variants and small insertions and deletions), the researchers combined significance levels from multiple methods of driver discovery. Additional analyses, led by other team members, focused on detecting structural variants (large rearrangements of DNA), based on novel methods for identifying regions with recurrent DNA breaks and repair.
Key Findings
- Certain known drivers were confirmed, but unexpectedly, few novel noncoding drivers were detected
- Interesting newly identified noncoding drivers did include 5′-end mutations in TP53, 3′ untranslated region mutations in NFKBIZ and TOB1
- Several previously reported noncoding elements seemed to be transcription-associated mutations, not genuine drivers
- New driver rearrangements involving AKR1C and BRD4
A New Focus for Development of Cancer Treatments
As growing numbers of cancer genomes become available, along with technological advances, new noncoding drivers will still be discovered. However, the ratio of coding to noncoding drivers is not expected to change substantially. Efforts to develop new cancer treatments will benefit from the innovations in this study and future novel noncoding drivers but will likely continue to focus on protein-coding sequences.
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