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What are we learning from the cancer genome?

Abstract

Massively parallel approaches to nucleic acid sequencing have matured from proof-of-concept to commercial products during the past 5 years. These technologies are now widely accessible, increasingly affordable, and have already exerted a transformative influence on the study of human cancer. Here, we review new features of cancer genomes that are being revealed by large-scale applications of these technologies. We focus on those insights most likely to affect future clinical practice. Foremost among these lessons, we summarize the formidable genetic heterogeneity within given cancer types that is appreciable with higher resolution profiling and larger sample sets. We discuss the inherent challenges of defining driving genomic events in a given cancer genome amidst thousands of other somatic events. Finally, we explore the organizational, regulatory and societal challenges impeding precision cancer medicine based on genomic profiling from assuming its place as standard-of-care.

Key Points

  • The past decade of studying the cancer genome has resulted in major breakthroughs in the treatment of cancers, such as leukaemias, breast and lung cancers and melanoma

  • Advances in sequencing now allow interrogation of cancer genomes both broadly, by assessing many genes in many samples, and deeply, by assessing variations within a specific gene in a single sample

  • A typical tumour may carry a few well-understood driver aberrations and tens to thousands of poorly understood aberrations that may collaborate in the development of each individual cancer phenotype

  • Organizing the myriad genomic aberrations in an individual tumour onto a limited number of affected pathways may guide development of pathway-targeted therapies

  • By expanding our definition of driver aberrations to include those that influence genome stability, chromatin structure, differentiation, RNA processing and beyond, we may increase successes in developing novel therapeutic strategies

  • Future challenges include data storage, distribution, analysis and the necessity to update regulatory models; developers, regulators, clinicians, patient advocates and others must approach this exciting time with flexibility and creativity

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Figure 1
Figure 2: Heterogeneity in cancer.
Figure 3: Mutation spectra define NOTCH1 as a tissue-specific bifunctional oncogene or tumour-suppressor gene.
Figure 4

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Acknowledgements

The authors thank Sam Ng, Josh Stuart and Barry Taylor for assistance, comments and figures. This work was supported by the National Institutes of Health, National Cancer Institute grant P50 CA 58207 and the U54 CA 112970, K08CA137153.

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Collisson, E., Cho, R. & Gray, J. What are we learning from the cancer genome?. Nat Rev Clin Oncol 9, 621–630 (2012). https://doi.org/10.1038/nrclinonc.2012.159

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