Genomics and the Continuum of Cancer Care — NEJM

Review Article

Genomic Medicine

W. Gregory Feero, M.D., Ph.D., Editor, Alan E. Guttmacher, M.D., Editor

Genomics and the Continuum of Cancer Care
Ultan McDermott, M.B., B.S., Ph.D., James R. Downing, M.D., and Michael R. Stratton, M.D., Ph.D.
N Engl J Med 2011; 364:340-350January 27, 2011


Assay of Tumor DNA to Detect Recurrence.
The provision of the human genome sequence in 20001 set in motion several waves of cancer research. The identification of an essentially complete set of protein-coding genes, coupled with the discovery of novel transcribed elements such as microRNAs (see the Glossary), has fostered an explosion of investigation using array-based approaches into patterns of gene expression in most cancer types. Similarly, the development of systematic approaches to identify somatic mutations has prompted exhaustive analyses of changes in cancer genomes, including copy-number changes (deletions and amplifications of DNA), rearrangements, small insertions and deletions, and point mutations.2 Recently, these efforts have culminated in the sequencing of complete genomes of human cancers, providing comprehensive catalogues of somatic mutations.3,4 These studies have yielded insights into the genes that contribute to cellular transformation.2 In parallel, the characterization of inherited variation in human populations has unleashed a surge of exploration into cancer susceptibility, focusing mainly on DNA variants that are common in the general population and that confer small increases in cancer risk. Finally, sets of biologic reagents have been developed that interfere with the function of essentially all genes in living cells, the most widely used being small interfering RNAs. These are being used in myriad ways — for example, to systematically determine which genes are required for cancer cells to survive and which genes confer sensitivity to particular drugs.

Some of the early fruits of this research, along with the techniques needed to implement them, are already being incorporated into clinical oncology. Here, we review the effects that genomic approaches are having on tumor classification, prognostic markers, predictive indicators of drug response, the development of new drug therapies, strategies for monitoring disease, and the management of susceptibility to cancer.

Biologic Classification
For most cancers, we still rely on histologic analysis of stained tissue sections or cells for diagnosis and subclassification. In some tumor types (e.g., breast cancers and the leukemias), molecular markers have been adjuncts to histologic classification for decades. The advent of microarray-based profiling, which measures the expression level of thousands of messenger RNA (mRNA) transcripts in a single experiment, has substantially increased the power to subclassify cancers. Possibly the most celebrated example has been the contribution of expression profiling to the classification of breast tumors.5 Although pathologists have long been aware of the heterogeneity of this disease, expression profiling has contributed to the development of a classification that usually includes the major molecular subtypes of basallike, positive for human epidermal growth factor receptor 2 (HER2), normal breastlike, luminal A, and luminal B. This classification is still evolving but has become a widely used conceptual framework in clinical breast oncology, with the different subtypes having markedly different clinical and biologic features, including patient survival.6,7 In routine clinical practice, however, classification is still based on conventional histologic analysis, coupled with immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), and HER2, which when combined can reconstruct most of the subclasses defined by mRNA expression.

Beyond refinement of tumor classification, how might these advances be used? An example of a standard clinical classification problem that conventional histologic analysis has often struggled to address is ascertainment of the primary tissue of origin of a metastatic cancer. Gene-expression signatures, however, can provide acuity of resolution beyond that of the microscope-aided human eye, and since elements of the expression pattern of the tissue of origin are often retained in the cancer, analysis of expression profiles, particularly those that include expressed microRNAs, often provide additional insight, although they are not currently used in routine clinical practice.8

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Genomics and the Continuum of Cancer Care — NEJM