Key Points
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Germline and somatic sequence variants in non-coding regions can play an important role in cancer.
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Many different modes of action of non-coding variants are known. For example, point mutations and complex genomic rearrangements can disrupt or create transcription factor-binding sites or affect non-coding RNA loci.
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Oncogenesis involves an interplay between germline and somatic variants.
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Drivers in non-coding regions can be identified using computational methods that analyse functional effects of variants and recurrence across multiple samples.
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Functional effects of non-coding variants can be studied by various experimental approaches.
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The overall role of non-coding variants in tumorigenesis is currently likely underestimated as only a handful of genome-wide studies of tumours have analysed them. However, current and future efforts involving large-scale whole-genome sequencing of tumours are likely to shed more light on the importance of non-coding variants in cancer.
Abstract
Patients with cancer carry somatic sequence variants in their tumour in addition to the germline variants in their inherited genome. Although variants in protein-coding regions have received the most attention, numerous studies have noted the importance of non-coding variants in cancer. Moreover, the overwhelming majority of variants, both somatic and germline, occur in non-coding portions of the genome. We review the current understanding of non-coding variants in cancer, including the great diversity of the mutation types — from single nucleotide variants to large genomic rearrangements — and the wide range of mechanisms by which they affect gene expression to promote tumorigenesis, such as disrupting transcription factor-binding sites or functions of non-coding RNAs. We highlight specific case studies of somatic and germline variants, and discuss how non-coding variants can be interpreted on a large-scale through computational and experimental methods.
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Acknowledgements
F.D. would like to acknowledge grant IG 13562 from AIRC (Associazione Italiana per la Ricerca sul Cancro).
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FURTHER INFORMATION
Glossary
- Exome sequencing
-
Sequencing the protein-coding portion of the genome using target-enrichment and high-throughput sequencing technology.
- Driver mutations
-
Sequence variants that confer growth advantage to tumour cells.
- Passenger mutations
-
Sequence variants that do not contribute to cancer growth.
- Germline variants
-
Heritable variants that are transmitted to offspring. These variants are constitutional (that is, present in all cells of the body).
- Genome-wide association studies
-
(GWASs). Studies that interrogate multiple common genetic variants along the genome in large cohorts of individuals to evaluate whether any variant is associated with a specific trait.
- Single nucleotide variants
-
DNA sequence changes at single nucleotides.
- Somatic variants
-
Variants that are not inherited from a parent and are not transmitted to offspring.
- Penetrance
-
The proportion of individuals carrying an allele (or a genotype) that also express the trait (phenotype) associated with it.
- Chromoplexy
-
(From the Greek pleko, meaning to weave, or to braid). A class of complex somatic DNA rearrangements whereby abundant DNA deletions and intra- and inter-chromosomal translocations that have originated in an interdependent way occur within a single cell cycle.
- Chromothripsis
-
(From the Greek thripsis, meaning shattering into pieces). A clustered chromosomal rearrangement in confined genomic regions that results from a single catastrophic event, usually limited to one chromosome.
- Kataegis
-
(From the Greek kataigis, meaning thunder). A phenomenon that is characterized by large clusters of mutations (hypermutation) in the genome of cancer cells. An APOBEC family enzyme might be responsible for the kataegis process.
- Cis-regulatory regions
-
Regions that regulate the expression of genes on the same DNA molecule. These include promoters, enhancers, silencers, insulators and untranslated regions.
- Enhancers
-
Distal cis-regulatory regions bound by transcription factors that activate genes by helping the recruitment of RNA polymerase to the promoters.
- Silencers
-
Distal cis-regulatory regions bound by transcription factors that repress gene expression by preventing RNA polymerase from binding to the gene promoter.
- Insulators
-
Regions that block the interaction between enhancers and promoters.
- DNase I footprinting
-
A method to detect the exact binding sites of DNA-binding proteins based on the fact that a protein bound to DNA protects it from cleavage by DNase I.
- Chromosome conformation capture
-
(3C). A biochemical method whereby the three-dimensional organization of chromatin in living cells is fixed and analysed.
- Expression quantitative trait loci
-
(eQTLs). Loci in which DNA sequence variants are related with expression levels of mRNAs.
- Endo-siRNAs
-
Endogenously produced small interfering RNAs that regulate gene expression by binding and cleaving mRNA targets or mediating heterochromatin formation.
- Negative selection
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Selective pressure that results in the removal of deleterious alleles.
- Single nucleotide polymorphisms
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(SNPs). Single nucleotide variants that show variability in the human population. As used in the context of this Review, they may be common (with high allele frequency) or rare (with low allele frequency).
- Oncogene
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A gene that is often upregulated in cancer and can lead to or promote cancer growth.
- Burden tests
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Statistical methods to test the cumulative effect of multiple variants in a genomic region.
- Positive selection
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Directed selection that forces the allele frequency of advantageous mutations to increase.
- Minigene assays
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Assays using a plasmid with a minimal gene fragment necessary for the gene to be expressed. It can include exons as well as introns, and it serves as a tool for evaluating splicing patterns.
- Precision medicine
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Medical care tailored to the individual patient, usually using the patient's genomic sequence.
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Khurana, E., Fu, Y., Chakravarty, D. et al. Role of non-coding sequence variants in cancer. Nat Rev Genet 17, 93–108 (2016). https://doi.org/10.1038/nrg.2015.17
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DOI: https://doi.org/10.1038/nrg.2015.17
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