High-throughput genome sequencing poised to impact cancer care

Sequencing tumor DNA in time to match patients with targeted therapy is quickly becoming a viable possibility for genomic medicine. The combination of relatively inexpensive high-throughput sequencing and increasing evidence of the potential inherent in understanding patterns of somatic mutation in individual cancer cases is being reported not only in journals but also in the public square. Beginning on July 7, the New York Times ran a series on personal genomics in cancer care, bringing genomic analysis of cancer to a large audience. The series raises a number of ethical issues about who should receive genomic tests and whether patients would even want to know results that offer no treatment options. The Washington University genomic team featured in the Times series published a paper in the June 10 issue of Nature showing in a retrospective analysis of estrogen receptor–positive breast cancer tumors that whole-genome analysis could predict responders to aromatase inhibitor therapy. Buried in Supplementary Table 18 of the paper, the authors match tumor mutations with existing targeted drugs, none of which are approved for treatment of breast cancer. The table highlights the problem of research findings getting ahead of approved uses of drugs, a dilemma poignantly laid out in the struggles of patients followed in the Times series. Perhaps the answer can be found in the Nature authors’ call for prospective clinical trials that include comprehensive genome sequencing to guide treatment. —Karyn Hede, News Editor

Whole-genome sequencing of fetal DNA

In a technical tour de force, Kitzman et al. (Sci Transl Med 2012;4:137ra76) recently carried out noninvasive whole-genome sequencing (WGS) of a human fetus. In one sense this represents the next logical extension of the application of massively parallel sequencing to clinical medicine. However, for several reasons, such application remains firmly in the research realm. As the authors acknowledge, major issues remain to be tackled before WGS can be implemented clinically in the prenatal setting.

The reality is that we, of course, don’t know how to interpret the vast majority of variants found in any given WGS. Given this lack of knowledge, coupled with the highly constrained timeline when dealing with analysis of fetal DNA, it is clear that WGS of fetal DNA for clinical purposes is a long way off. Not only is the timeline difficult, but the stakes are high with regard to interpreting fetal variants. Many individuals who seek fetal genetic analysis are doing so to help them decide about termination of pregnancy. Therefore, the implications of both false-negative and false-positive results (of which there were many in this experiment) loom large, and we will need to get much better at interpretation before we can offer parents reliable guidance through the use of this type of analysis.

The targeted application of such technology, though, is already finding its way into the clinic. At least three labs in the United States are offering noninvasive fetal DNA analysis via next-generation sequencing for the detection of trisomies, and there is no reason why, in principle, targeted noninvasive mutational analysis of fetal DNA for any given target gene could not be performed in this way. But, as always, the application of any such technology in the prenatal setting will require navigating a host of less tangible issues related to reproductive and fetal rights. —James P. Evans, Editor-in-Chief

Genetics in Medicine Mission Statement

Genetics in Medicine is a monthly journal committed to the timely publication of:

  • Original reports which enhance the knowledge and practice of medical genetics

  • Strategies and innovative approaches to the education of medical providers at all levels in the realm of genetics

As the official journal of the American College of Medical Genetics and Genomics (ACMG), the journal will:

  • Provide a forum for discussion, debate and innovation concerning the changing and expanding role of medical genetics within the broader context of medicine

  • Fulfill our responsibility to the College membership through the publication of guidelines, policy statements and other information that enhances the practice and understanding of medical genetics

Finally, as genetics becomes increasingly important in the wider medical arena, we will be an accessible and authoritative resource for the dissemination of medical genetic knowledge to providers outside of the genetics community through appropriate reviews, discussions, recommendations and guidelines.