Key Points
The emergence of next-generation sequencing technology has made important contributions to our understanding of cancer genomes.
In this Review, we present a current view of the mutational landscapes of diverse cancer types.
There are various challenges to identifying driver mutations and functionally validating significantly mutated genes.
Whole-exome and whole-genome sequencing studies, and integrative analysis with other genomic platforms have provided biological insights into the aetiology of cancer.
Such studies are enabling the classification of cancers on the basis of genetic alterations rather than of tissue of origin.
Abstract
Recent advances in technological tools for massively parallel, high-throughput sequencing of DNA have enabled the comprehensive characterization of somatic mutations in a large number of tumour samples. In this Review, we describe recent cancer genomic studies that have assembled emerging views of the landscapes of somatic mutations through deep-sequencing analyses of the coding exomes and whole genomes in various cancer types. We discuss the comparative genomics of different cancers, including mutation rates and spectra, as well as the roles of environmental insults that influence these processes. We highlight the developing statistical approaches that are used to identify significantly mutated genes, and discuss the emerging biological and clinical insights from such analyses, as well as the future challenges of translating these genomic data into clinical impacts.
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Acknowledgements
The authors apologize for the omission of any pertinent work related to this Review. They thank D. Spring and members of the Chin laboratory for their comments and feedback. I.R.W. is a recipient of the Canadian Institutes of Health Research Fellowship; K.T. is supported by the Kimberly Patterson Leukemia Fellowship and Celgene Future Leaders in Hematology Award; L.C. and P.A.F. are recipients of the Cancer Prevention and Research Institute of Texas (CPRIT) Established Investigator Recruitment Award. This project was supported by CPRIT and Grant Number U24CA143845 from the US National Cancer Institute (NCI). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NCI or the US National Institutes of Health.
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Supplementary information S1 (figure)
Recurrent and significantly mutated genes identified from analysis of whole-exome and whole-genome sequencing studies of solid tumours. (PDF 163 kb)
Supplementary information S2 (figure)
Recurrent and significantly mutated genes identified from analysis of whole-exome and whole-genome sequencing studies of haematologic malignancies. (PDF 140 kb)
Glossary
- Next-generation sequencing
-
(NGS). All post-Sanger DNA sequencing methods, most commonly referring to massively parallel sequencing technology.
- Hybrid-capture
-
A target enrichment approach in which custom oligonucleotides (the bait set) are designed and optimized to hybridize to specific regions of the genome so that specific fragments of DNA can be enriched by hybridization for next-generation sequencing.
- Whole-exome sequencing
-
(WES). Next-generation sequencing of all protein- coding exomes after capture, using hybridization to a whole-exome bait set designed to enrich DNA in all protein-coding portions of the genome. The most common implementation also targets microRNA genes. The size of the captured DNA is approximately 40 Mb.
- Whole-genome sequencing
-
(WGS). Sequencing of the entire genome, usually by random fragmentation (shotgun) and to sufficient coverage so as to ensure adequate representation of all alleles. A variation specifically using low-coverage WGS is sometimes used to assess rearrangements in the genome.
- Cancer genes
-
Genes that harbour cancer-driving genetic aberrations (however, cancer genes may possess both driver and passenger somatic alterations) as defined by criteria including statistical evidence of selection and recurrence pattern, or by functional activity.
- Chromothripsis
-
Greek for chromosome 'shattering', in which up to hundreds of genomic rearrangements take place in a single cellular crisis event that develops from errors in mitosis that occur in ~2–3% of cancers.
- Chromoplexy
-
Greek for chromosome 'weave' or 'braid'. A process whereby a closed chain of chromosomes is formed by copy-neutral rearrangements that consist of 4–12 distinct breakpoint junctions, which tend to occur at transcriptionally active portions of chromatin.
- Kategeis
-
Greek for 'shower' or 'thunderstorm'. A phenomenon, identified in breast cancers, of localized hypermutations almost exclusively involving cytosine base pair substitutions at TpC dinucleotides. This mutation pattern has been linked to the APOBEC family of cytidine deaminases.
- Driver mutations
-
Somatic mutations in a gene that confer a selective advantage on cancer cells as reflected in the statistical evidence of positive selection. This is not a definition based on functional activity.
- Significantly mutated genes
-
(SMGs). Genes that have a somatic mutation rate above the calculated background mutation rate as determined by a given statistical calculation.
- Background mutation rate
-
(BMR). The rate of mutation in a tumour sample as a consequence of exposure to environmental mutagens (for example, ultraviolet radiation) and/or random generation and misrepair processes.
- RNA sequencing
-
(RNA-seq). Whole-transcriptome shotgun sequencing of cDNA to determine the sequence of RNA; used for expression analysis and the identification of gene–gene fusions.
- Two-hit tumour suppressor
-
Refers to the necessity to inactivate both alleles of a tumour suppressor gene, following the Knudson two-hit hypothesis, which was proposed to explain the early onset of cancer in hereditary syndromes in which the inheritance of one germline copy of a mutated gene in all cells substantially increases the likelihood of any cell acquiring a mutation in the other allele.
- Passenger mutations
-
Neutral mutations in a gene that do not provide a selective advantage for cancer cells as reflected by the lack of statistical evidence for positive or negative selection. This is not a definition based on functional activity.
- Hotspot mutation
-
A recurrent mutation resulting in the same amino acid change in a gene observed in cancer, signifying strong positive selection.
- CpG island methylator phenotype
-
A classification of cancers by their degree of methylation at CpG-rich promoter regions, first characterized in human colorectal cancers; often associated with distinct epidemiological, histological and molecular features.
- Microsatellite instability
-
(MSI). A hypermutable phenotype caused by germline, somatic or epigenetic inactivation in DNA mismatch repair activity.
- Epstein–Barr virus
-
(EBV). A member of the Herpes virus family that is associated with the development of particular forms of cancer.
- Triple-negative breast cancer
-
(TNBC). One of the subtypes of breast cancer that is defined by the absence of staining for oestrogen receptor, progesterone receptor and ERBB2 by immunohistochemistry.
- Neoadjuvant aromatase inhibitors
-
Used to treat patients with oestrogen receptor-positive breast cancer before surgical resection and is applied in cases in which tumour size needs to be reduced for breast-conserving surgery. This treatment is not currently considered as a standard of care and is conducted under clinical trials.
- Sleeping Beauty transposon mutagenesis
-
A genetically engineered insertional mutagenesis system involving synthetic DNA transposons, which can be applied to various model systems to ascertain gene function.
- Aflatoxin B
-
One of the mycotoxins that are produced by Aspergillus Flavus. High-level exposure to aflatoxins is known to cause acute liver necrosis or cirrhosis, resulting in the development of hepatocellular carcinoma.
- French–American–British (FAB) classification
-
First proposed in 1976 by the French–American–British cooperative group and updated in 1989, it classified acute myeloid leukaemia into eight different categories (M0–M7) and acute lymphoblastic leukaemia into three different categories (L1–L3) based on their morphological findings.
- Actionable genetic alterations
-
Genetic alterations with sufficient scientific evidence supporting their use to inform treatment decisions.
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Watson, I., Takahashi, K., Futreal, P. et al. Emerging patterns of somatic mutations in cancer. Nat Rev Genet 14, 703–718 (2013). https://doi.org/10.1038/nrg3539
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DOI: https://doi.org/10.1038/nrg3539
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