Whole-genome sequencing in medicine: New knowledge, new responsibilities

(Karl-Ludwig Poggemann/Wikimedia Commons)

Recently, in the hospital cafeteria, I overheard a group of researchers discussing the upcoming availability of whole-genome sequencing to physicians. “We should devise a way to study how physicians will use this,” said one of them—underscoring the disruptive nature of the transformation that is currently happening in medicine.

The ability to immediately obtain whole-genome sequences from patients holds enormous potential for understanding and treating human disease. The list of studies reporting successful diagnosis of otherwise elusive orphan conditions is already too long to recount—more than 600 articles in PubMed as of the date of this posting—including poignant examples of advancing clinical care. Some are transformative achievements, such as a recently published study that identified mutations causing a complex childhood movement disorder. Whole-genome sequencing not only yielded a fundamentally novel biologic discovery, but also led to an effective therapy, resulting in clinical improvements in both patients in the study.

However, widespread use of whole-genome sequencing comes with novel responsibilities. It can yield unexpected results, which will need to be communicated to patients responsibly. The CLARITY contest, announced by Children’s yesterday, is an excellent start: Companies will compete to interpret DNA sequence information from three patients and report it in a form that a physician can easily use to guide patient counseling and care.

By virtue of producing an individual’s unique DNA sequence, clinical use of whole-genome sequencing will create other challenges: how to maintain individual privacy and confidentiality.

The recent decision by the National Collegiate Athletic Association to impose mandatory screening of athletes for sickle cell trait is just one example of how knowledge of the genetic basis of disease may be used outside of medicine. Similar information can be used by health insurance companies to decide insurance eligibility and prices, by employers to guide hiring practices (no matter how illegal), and by individuals to select mates or decide the fate of a pregnancy. Because whole-genome sequences correspond uniquely to each individual, the distribution of whole genome sequencing data for research purposes is tightly regulated, requiring users to be authorized by the National Institutes of Health and to abide by a strict Code of Conduct.

However frightening privacy abuses may be, the more daunting challenge is to integrate the sequencing results of many individuals. This integration is essential since only 1 percent of the 3 billion nucleotides of the human genome contain genes, and only a fraction of these have known functions in human physiology. A full understanding of their function and contribution to disease requires integrating genomic data across currently distinct medical specialties. An oncologist seeking to understand the genetic predisposition for the development of a particular tumor needs access to test results from other individuals with that tumor, but understanding what the sequence variants mean for other diseases requires access to still more individuals and their clinical records.

Add to that the fact that analysis of the whole-genome sequencing data is never completely finished, as illustrated by the recent example of a patient with acute myeloid leukemia (AML). The original analysis, reported in 2008, found 10 genes with mutations. A subsequent analysis reported in 2010, using improved methods, identified additional mutations, including one in a fundamental gene found not just in the original patient but in more than 20 percent of adult patients with AML. This discovery opened important areas of clinical and basic research, and potentially new therapeutic approaches.

Overzealous controls on the use of whole-genome sequencing have the potential to curtail such advances. Data integration and future testing require explicit consent from patients, often years and even decades before the questions and tools for performing such analyses are developed. Current practices by the Institutional Review Boards that regulate biomedical research limit investigators’ ability to contact study participants to discuss test results and solicit further information. Yet, this communication is crucial to avoid unapproved use of genetic samples, as emphasized by the recent legal settlement involving the Havasupai Indian tribe, and to return potentially useful knowledge to patients.

Currently, health providers from all fields of medicine, like my cafeteria neighbors, are asking the same question: How will we use whole-genome sequencing in our practice? Hospitals, physicians and scientists will need to educate themselves and their patients about the potential benefits and risks of this emerging technology.

Alex Kentsis, MD, PhD, is a pediatric hematologist-oncologist at the Dana-Farber/Children’s Hospital Cancer Center who is applying translational genomic and proteomic technologies to advance the treatment of children with tumors and inflammatory diseases.