Editors' ChoiceCancer

Shedding Light on the Genome’s Dark Matter

See allHide authors and affiliations

Science Translational Medicine  08 Oct 2014:
Vol. 6, Issue 257, pp. 257ec173
DOI: 10.1126/scitranslmed.3010422

When scientists search for genetic mutations that cause human disease, they tend to look in protein-coding DNA, which comprises the exons of known genes. Interpreting the impact of a genetic change in an exon, which can be related to a subsequent change in the protein, is straightforward. Indeed, the vast majority of known disease-causing mutations lie within protein-coding DNA, even though it makes up only 1 to 2% of the human genome. The remaining 98% of the genome is often referred to as “dark matter.” The function of the DNA sequence in this dark matter is less clear, and interpreting the effect of a genetic change is difficult. Recent projects such as the Encyclopedia of DNA Elements (ENCODE) have made substantial progress in annotating the dark matter, assigning putative functions to many regions such as the promoters, enhancers, repressors, and transcription factor binding sites of genes. This effort should accelerate the interpretation of noncoding changes, facilitating mutation discovery in patients and in diseases in which coding mutations cannot be identified.

Weinhold and colleagues take advantage of whole-genome sequencing data from paired tumor and normal tissue samples to investigate the role of noncoding mutations in cancer. They identified noncoding DNA mutations in tumor DNA compared with normal tissue from the same individual in 863 cancer patients. Using three different approaches, they identified regions of noncoding DNA where mutations in the tumor samples seemed to cluster. A search for “hotspots” revealed two recurrent mutations upstream of PLEKHS1, a gene not previously implicated in cancer, as well as several near genes that are known to be associated with cancer. Targeted analysis of annotated regulatory regions identified several genes with frequent promoter or 5′ untranslated region mutations, including WDR74, near which 4% of samples harbored a noncoding mutation. Last, they looked specifically for mutations that created or destroyed a binding site for the transcription factor, ETS, again identifying an enrichment of this class of mutation upstream of some genes. Importantly, the authors could also show in some cases that the noncoding DNA mutation correlated with a change in gene expression, suggesting that at least some have a functional effect.

There is no question that noncoding mutations will play an important role in human disease. This comprehensive analysis by Weinhold and colleagues sheds light on noncoding mutations in cancer. Further investigation of the types and locations of noncoding mutations that are related to disease in this study may also lend insight into the interpretation of similar mutations in other genetic disorders.

N. Weinhold et al., Genome-wide analysis of noncoding regulatory mutations in cancer. Nat Genet. 10.1038/ng.3101 (2014). [Abstract]

Stay Connected to Science Translational Medicine

Navigate This Article