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Non-coding driver mutations in human cancer

Abstract

Tumour formation involves random mutagenic events and positive evolutionary selection acting on a subset of such events, referred to as driver mutations. A decade of careful surveying of tumour DNA using exome-based analyses has revealed a multitude of protein-coding somatic driver mutations, some of which are clinically actionable. Today, a transition towards whole-genome analysis is well under way, technically enabling the discovery of potential driver mutations occurring outside protein-coding sequences. Mutations are abundant in this vast non-coding space, which is more than 50 times larger than the coding exome, but reliable identification of selection signals in non-coding DNA remains a challenge. In this Review, we discuss recent findings in the field, where the emerging landscape is one in which non-coding driver mutations appear to be relatively infrequent. Nevertheless, we highlight several notable discoveries. We consider possible reasons for the relative absence of non-coding driver events, as well as the difficulties associated with detecting signals of positive selection in non-coding DNA.

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Fig. 1: Mechanisms by which non-coding mutations can contribute to tumorigenesis.
Fig. 2: Sources of heterogeneity in genomic mutation rate for consideration when assessing signals of selection in non-coding DNA.
Fig. 3: Local vulnerability to ultraviolet mutagenesis at ETS-binding sites is a characteristic feature of strong mutation hotspots in melanoma.
Fig. 4: Top recurrently mutated protein-coding and non-coding elements in PCAWG.

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Acknowledgements

E.L. is supported by grants from the Knut and Alice Wallenberg Foundation, the Swedish Medical Research Council and the Swedish Cancer Society.

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K.E. and E.L. both researched data for the article and made a substantial contribution to discussion of content, writing, reviewing and editing the article.

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Correspondence to Erik Larsson.

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Nature Reviews Cancer thanks J. Wong, A. Gonzalez-Perez and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

ActiveDriverWGS: https://cran.r-project.org/web/packages/ActiveDriverWGS/vignettes/ActiveDriverWGSR.html

CNCDriver: https://github.com/khuranalab/CNCDriver

COSMIC Cancer Gene Census: https://cancer.sanger.ac.uk/census

Driver Power: https://github.com/smshuai/DriverPower

ExinAtor: https://github.com/alanzos/ExInAtor/

fishHook: https://github.com/mskilab/fishHook

ICGC: https://dcc.icgc.org

LARVA: http://larva.gersteinlab.org/

MOAT: http://moat.gersteinlab.org/

MutEnricher: https://github.com/asoltis/MutEnricher

MutSigCV: https://software.broadinstitute.org/cancer/cga/mutsig

MutSpot: https://github.com/skandlab/MutSpot

ncdDetect2: http://moma.ki.au.dk/ncddetect/

ncDriver: http://moma.ki.au.dk/ncDriver/

OncodriveFML: http://bbglab.irbbarcelona.org/oncodrivefml/home

regDriver: https://github.com/husensofteng/regDriver

SMuRF: https://github.com/LupienLab/SMURF

TCGA: https://gdc.cancer.gov

UCSC Genome Browser: https://genome.ucsc.edu/

Glossary

Point mutations

Single-base changes in the genome.

Indels

Small insertions or deletions of DNA bases.

Enhancer

A distal regulatory region bound by transcription factors that aids recruitment of polymerases.

Passenger mutations

DNA alterations that do not provide a growth advantage.

Structural variants

Genomic alterations, such as gene duplications, translocations or inversions, affecting a large chromosomal segment, typically greater than 1 kb.

Neutral selection

Neither positive nor negative selection, that is, lacking influence on cell fitness.

Heterochromatin

DNA in a tightly packed and condensed form, marked by H3K9 methylation.

Cyclobutane pyrimidine dimer

The principal ultraviolet-induced DNA damage lesion, resulting from dimerization of neighbouring pyrimidines.

MicroRNA

A small regulatory RNA (around 22 bp) that can alter gene expression through mRNA silencing.

Topologically associating domain

A genomic segment showing a high degree of within-region physical interaction.

COSMIC Cancer Gene Census

A list of approximately 700 genes known to be mutated and have functional roles in cancer, compiled from decades of research.

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Elliott, K., Larsson, E. Non-coding driver mutations in human cancer. Nat Rev Cancer 21, 500–509 (2021). https://doi.org/10.1038/s41568-021-00371-z

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