NEJM -- Genomic Medicine -- An Updated Primer

Volume 362:2001-2011 May 27, 2010 Number 21

Genomic Medicine — An Updated Primer

W. Gregory Feero, M.D., Ph.D., Alan E. Guttmacher, M.D., and Francis S. Collins, M.D., Ph.D.

Cathy, a 40-year-old mother of three, arrives in your office for her annual physical. She has purchased a commercial genomewide scan (see the Glossary at the end of this article), which she believes measures the clinically meaningful risk that common diseases will develop, and has completed her family history online using My Family Health Portrait (www.familyhistory.hhs.gov), a tool developed for this purpose by the U.S. Surgeon General. Her genomewide scan suggests a slightly elevated risk of breast cancer, but you correctly recognize that this information is of unproven value in routine clinical care. On importing Cathy's family-history file, your office's electronic health record system alerts you to the fact that Cathy is of Ashkenazi Jewish heritage and has several relatives with breast cancer, putting her at heightened risk for the hereditary breast and ovarian cancer syndrome. The system prompts you to discuss Cathy's risk of breast and ovarian cancer during the visit. Considering both her family history and ancestry, you refer Cathy to a health care professional with advanced genetics training for consultation.

In the coming months Cathy elects to have her DNA tested for mutations in BRCA1 and BRCA2, the genes associated with hereditary breast and ovarian cancer syndrome, and to undergo a mammographic examination. Although the results of her genetic tests are negative, her mammogram reveals a suspicious abnormality. A biopsy is performed, and breast cancer is detected. Surgery is successful. Pathological examination of tissue from the excised tumor reveals that it is positive for estrogen-receptor protein and negative for human epidermal growth factor receptor type 2 (HER2); the lymph glands are free of cancer cells. Genetic-expression profiling of the tumor indicates a relatively high risk of recurrent cancer, and Cathy elects to receive adjuvant chemotherapy followed by treatment with tamoxifen. Five years later, the cancer has not recurred.

Remarkable advances have been made in understanding the human genome's contribution to health and disease since the first Genomic Medicine series was launched in the Journal in 2002.1,2 The vignette about Cathy illustrates the strengths and limitations of these advances. Completion of the Human Genome Project in 20033,4 was a major driver for the current period of biomedical discovery, and the pace continues to accelerate. This project spurred the development of innovations with extraordinary benefits. Initially, clinically useful discoveries derived from the Human Genome Project yielded improvements in "genetic medicine" — that is, the use of knowledge about single genes to improve the diagnosis and treatment of single-gene disorders. However, our increased understanding of the interactions between the entire genome and nongenomic factors that result in health and disease is paving the way for an era of "genomic medicine," in which new diagnostic and therapeutic approaches to common multifactorial conditions are emerging.

As a result of genomic discoveries, increasing numbers of clinical guidelines now suggest incorporating genomic tests or therapeutics into routine care. In some cases, the rapidity of translation has sparked debate regarding the level of evidence of clinical benefit needed to introduce new, and potentially costly, medical technologies.5,6 Although the effect of genomic discovery on the day-to-day practice of medicine has not been well quantified, it probably remains small in primary care and nonacademic settings as compared with, for example, oncology practice in an academic medical center. Regardless of where medicine is practiced, genomics is inexorably changing our understanding of the biology of nearly all medical conditions. How can any clinician understand the diagnosis and treatment of breast cancer, much less explain it to a patient such as Cathy, without a rudimentary understanding of genomic medicine?

Here, laying the groundwork for the rest of this series, we review key conceptual and technological advances in genomics that have occurred since the first series appeared in 2002. Readers who wish to review core principles of genetics and genomics are encouraged to revisit that first primer.1 A glossary of key terms appears in this article and will be updated throughout the course of the Genomic Medicine series.

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NEJM -- Genomic Medicine -- An Updated Primer