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The molecular pathology of cancer

Nature Reviews Clinical Oncology volume 7, pages 251–265 (2010)Cite this article

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Abstract

Rapid technical advances in DNA sequencing and genome-wide association studies are driving the discovery of the germline and somatic mutations that are present in different cancers. Mutations in genes involved in cellular signaling are common, and often shared by tumors that arise in distinct anatomical locations. Here we review the most important molecular changes in different cancers from the perspective of what should be analyzed on a routine basis in the clinic. The paradigms are EGFR mutations in adenocarcinoma of the lung that can be treated with gefitinib, KRAS mutations in colon cancer with respect to treatment with EGFR antibodies, and the use of gene-expression analysis for ER-positive, node-negative breast cancer patients with respect to chemotherapy options. Several other examples in both solid and hematological cancers are also provided. We focus on how disease subtypes can influence therapy and discuss the implications of the impending molecular diagnostic revolution from the point of view of the patients, clinicians, and the diagnostic and pharmaceutical companies. This paradigm shift is occurring first in cancer patient management and is likely to promote the application of these technologies to other diseases.

Key Points

  • Rapid technical advances in DNA sequencing and other molecular analysis tools are driving the discovery of somatic mutations involved in the development and progression of cancer

  • Many of the same signaling pathways are mutated in different cancers, such as KRAS mutations, which frequently occur in both colon and lung cancer

  • Understanding the mutation profile of individual tumors has allowed the development of tailored treatments, such as EGFR tyrosine kinase inhibitors in lung cancer patients with EGFR mutations

  • Gene-expression profiling is being used to identify patients with tumors that can be treated distinctly; for example, gene-expression arrays can help determine which breast cancer patients would benefit from chemotherapy

  • Molecular profiling is being carried out for most cancers and will lead to a new breed of molecular pathologists in the field of oncology

  • The implications of the molecular pathology revolution are profound for both the cancer patient and the health care system

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Figure 1: EGFR signaling and related pathways.
Figure 2: Important mutated pathways in lung adenocarcinomas.
Figure 3: Germline mutations that confer susceptibility to breast cancer.

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Acknowledgements

The authors would like to thank Drs Javed Khan, David Munroe, Bob Stephens, Lou Staudt, Snorri Thorgeirsson and Mickey Williams for providing information and for helpful comments on the manuscript. The authors would like to apologize for not including references to some of the original work cited herein. This was for space limitation reasons only. This project has been funded in whole or in part with federal funds from the National Cancer Institute and National Institutes of Health (contract number HHSN261200800001E). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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  1. SAIC-Frederick, National Cancer Institute at Frederick, 1050 Boyles Street/PO Box B, Frederick, 21702, MD, USA

    Timothy J. R. Harris

  2. Helen Diller Family Cancer Research Building, Room 371, University of California San Francisco, 1450 3rd Street, San Francisco, 94158, CA, USA

    Frank McCormick

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Correspondence to Timothy J. R. Harris.

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T. J. R. Harris has worked as a consultant for Bionomics and BG Medicine, and is also a director of BG Medicine. F. McCormick is a director of Exelixis. He is also a director of Onyx and has worked as a consultant for this company. F. McCormick has also received research support from Daiichi Sankyo.

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Harris, T., McCormick, F. The molecular pathology of cancer. Nat Rev Clin Oncol 7, 251–265 (2010). https://doi.org/10.1038/nrclinonc.2010.41

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