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In This Case…

As a review published this week in the New England Journal of Medicine indicates, genome sequencing is coming to the clinic. While that review focused on how to use such tools to diagnose rare genetic disorders, a separate set of essays in the medical journal mulls the genetic testing or sequencing of a healthy individual worried about disease risk.

In the scenario described in NEJM, a health-conscious 45-year-old man learns after visiting cousins in Europe that some of his relatives have suffered form cancer, namely an aunt of breast cancer, an uncle of prostate cancer, and another female relative of ovarian cancer. The patient relays this new family history data to his physician and asks about genetic testing and "any preventive measures he can take 'before the cancer gets me.'"

After presenting the scenario, NEJM asks readers to weigh in on whether or not the man should undergo testing and, if so, whether he should be tested using a gene panel, whole-exome sequencing, or whole-genome sequencing.

The University of Washington's Wylie Burke, in an associated essay, recommends targeted sequencing of cancer genes only, but only if certain conditions are met. For instance, she says more information is required about how those relatives are related to one another, whether or not they are all in the same biologic line. Then, she adds, the next step would be to determine who the person to test is — it might be best, she says, to test an affected family member or someone from that side of the family.

"In keeping with the principle of focusing testing on the clinical question, the best testing approaches would either use a targeted gene sequencing panel, testing comprehensively for mutations in genes known to be associated with inherited breast and prostate cancer risk, or start with BRCA1/2 testing and proceed to more comprehensive testing if the results are normal," she adds.

David Dimmock from the Medical College of Wisconsin, by contrast, recommends whole-genome sequencing of the patient, again only if an affected family member cannot be located. Whole-genome sequencing, he argues, has technical and other advantages over gene-panel tests and whole-exome sequencing as it can better detect deletions and rearrangements and includes introns. Whole-genome sequencing, he adds, would also allow for the discovery of additional clinically relevant findings that could, if the patient develops cancer or another disease, inform treatment.

"Beyond the advantages of whole-genome sequencing in identifying a predisposition to cancer and informing therapeutic choices, whole-genome sequencing has the potential to provide information on the genetic risk of other diseases, such as hemochromatosis or disorders of lipid metabolism," he adds. "Such results have the potential to improve or refine risk-prevention strategies for the patient."

NEJM is asking its readers to consider these options and has a poll open until July 2 for people to log their choices.