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Towards systematic functional characterization of cancer genomes

Nature Reviews Genetics volume 12, pages 487–498 (2011)Cite this article

Subjects

Key Points

  • Cancer genome characterization efforts will provide a complete description of genetic and epigenetic alterations in cancer. However, the complexity and heterogeneity of cancer genomes makes it clear that complementary efforts to understand the function of cancer genes are necessary.

  • The tools to manipulate gene function at genome scale are now available in multiple formats. Technical advances will increase the power and throughput of these approaches.

  • Important functional-genomics approaches include systematic mutagenesis, RNAi, expression libraries and small-molecule screens.

  • Integration of functional and structural characterizations of cancer genomes provides a path to identifying driver genes.

  • These same approaches, tools and methods can also be used to study other diseases.

Abstract

Whole-genome approaches to identify genetic and epigenetic alterations in cancer genomes have begun to provide new insights into the range of molecular events that occurs in human tumours. Although in some cases this knowledge immediately illuminates a path towards diagnostic or therapeutic implementation, the bewildering lists of mutations in each tumour make it clear that systematic functional approaches are also necessary to obtain a comprehensive molecular understanding of cancer. Here we review the current range of methods, assays and approaches for genome-scale interrogation of gene function in cancer. We also discuss the integration of functional-genomics approaches with the outputs from cancer genome sequencing efforts.

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Figure 1: Overview of cancer functional genomics.
Figure 2: Tools and formats of cancer functional-genomics experiments.
Figure 3: Integrating functional and structural cancer genomics.

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Acknowledgements

We thank the members of the Hahn laboratory and the Broad Institute Cancer Program for discussions. W.C.H. is supported in part by grants from the US National Institutes of Health, the Starr Cancer Consortium, the Ivy Foundation, the H.L. Snyder Foundation and the Prostate Cancer Foundation. We apologize to those authors whose relevant work could not be cited owing to space considerations.

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Authors and Affiliations

  1. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Jesse S. Boehm & William C. Hahn

  2. Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana 1538, Boston, 02115, Massachusetts, USA

    William C. Hahn

  3. Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, 02115, Massachusetts, USA

    William C. Hahn

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  1. Jesse S. Boehm
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Correspondence to William C. Hahn.

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William C. Hahn is a consultant for Novartis Pharmaceuticals.

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Glossary

Oncogenes

Genes that are somatically mutated or amplified in tumours, are required for the survival of tumours that harbour the oncogene and cause transformation in a cell or animal model.

Tumour suppressor genes

Genes that show loss of heterozygosity in tumours and usually regulate cell survival.

Open reading frame

(ORF).The coding sequence of a transcript without 5′ or 3′ sequences.

RNA interference

(RNAi). The process by which endogenous or exogenous dsRNA molecules lead to interference with gene expression.

Functional-genomics studies

The manipulation of gene expression or function at large scale, usually using high-throughput approaches.

Transposons

DNA elements that can move to new positions within the genome of a single cell.

Short interfering RNAs

(siRNAs). RNA molecules that are capable of inducing RNA interference.

MicroRNAs

(miRNAs). MicroRNAs are short RNA molecules that regulate gene expression through gene silencing and translational repression.

Short hairpin RNAs

(shRNAs). An RNA interference-inducing molecule that folds back onto itself to create a hairpin structure.

Arrayed screens

Functional-genomics screens in which perturbations are individually performed.

Off-target effects

A term that refers to a phenotype that is not related to perturbation of the intended target of a short interfering RNA (siRNA) or small molecule.

Transformation

The process by which a normal cell acquires cellular phenotypes of a cancer cell.

Pooled screen

A functional-genomics screen in which genetic tools are mixed and administered to a cellular population under a selective pressure.

Aniokis

A form of cell death that is associated with loss of cell–matrix interactions.

RAS

A family of small GTPases that are frequently mutated in cancer. Single-nucleotide substitutions lead to constitutive activation of ras signalling.

Perturbagens

Small molecules, peptides, cDNAs or RNAi inducers that disrupt biological processes.

Synthetic lethal

A relationship between two genes in which the combined inactivation of the genes results in lethality, whereas the inactivation of either gene alone has no effect. It can also refer to a gene whose perturbation only results in lethality in the presence of a particular cellular feature (for example, mutation).

Structural genomics

Genome-wide approaches for cataloguing structural changes (for example, mutations and copy-number changes) in the genome.

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Boehm, J., Hahn, W. Towards systematic functional characterization of cancer genomes. Nat Rev Genet 12, 487–498 (2011). https://doi.org/10.1038/nrg3013

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