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Charting a course for genomic sequencing in patient care

NHGRI-funded CSER investigators, colleagues point to need for greater evidence that DNA sequencing helps patients

Doctor with a young patient in a hospital bedIn the nearly four years since its launch, the Clinical Sequencing Exploratory Research (CSER) program has made significant strides in defining the role of genomics in medicine. CSER investigators have discovered genomic variants - differences in the DNA code - that could contribute to disease; improved the analysis and interpretation of DNA sequencing results; and provided new insights into the ethical, legal and social implications of using genomics in clinical care.

CSER - which is funded by the National Human Genome Research Institute (NHGRI) and the National Cancer Institute, both parts of the National Institutes of Health - is nearing the end of its first round of research awards. To help identify the direction of a potential follow-up program, CSER investigators and colleagues recently met in Bethesda, Maryland, for a one-day conference, Integrating Genomic Sequencing into Clinical Care: CSER and Beyond.

The meeting focused on the program's goals and accomplishments, and on prioritizing future challenges and opportunities that could be addressed in a clinical sequencing program over the next 5 to 10 years. To strengthen the case for using genomic sequencing in the clinic, for example, speakers thought it was imperative to continue to build evidence linking genetic make-up to disease, and better understand the relation between genomic sequencing use and disease outcomes. Others stressed the importance of improving standards for determining what variants do and their roles in a patient's condition. Meeting participants recommended more studies of the impact on patients and families of diagnoses from genomic testing, and how that information is presented to them.

"CSER examines what a patient's genomic information really means to the patient and his or her family. It also looks at how patients' interactions with healthcare practitioners and clinical laboratories inform how genomic information should be applied in clinical care," said Lucia Hindorff, Ph.D., CSER program director in the Division of Genomic Medicine at NHGRI.

While many of the presentations looked to the future, the potential impact of some CSER research has been more immediate. In one study, investigators at the University of Michigan found benefits to DNA sequencing in childhood cancer. In another example, University of North Carolina at Chapel Hill researchers used DNA sequencing to help diagnose and treat a woman with dystonia, a painful muscle disorder. Dana-Farber Cancer Institute scientists in Boston developed a computer program to sort out and rank a patient's genomic mutations and variants according to what matters to a cancer, possibly helping guide treatment.

From proving DNA sequencing matters to dealing with unexpected results

During one meeting session, researchers discussed the need for evidence that clinical DNA sequencing makes a difference in patient care. Before doctors, patients and health care systems support the use of DNA sequencing, investigators say, clinicians need evidence that it can improve care and be cost- and time-effective compared to other approaches.

Heidi Rehm, Ph.D., director of the Laboratory for Molecular Medicine at Partners Healthcare and Brigham and Women's Hospital in Boston, said that a comprehensive resource describing the clinical relevance of genes and variants is only beginning to be developed. CSER has opportunities to build an "evidence base" for the use of genomics - and genomic testing - in patient care, she added.

At present, there are limited recommendations for what doctors can do with information about a disease-causing variant or gene mutation. It is a challenge, Dr. Rehm said, to accurately define a patient's disorder, and understand the role of the variants found in DNA sequencing.

"We need to develop new tools and standards for genomic testing. Labs should work together, share data and standardize the interpretation of what variants mean and how they cause disease," Dr. Rehm said.

Several speakers addressed the need to improve this interpretation. All too often, they said, researchers are left with an unsatisfying and inconclusive result, termed a "variant of uncertain significance." 

"To be effective and safe with genomic medicine, we need to know what variants do," said Gail Jarvik, M.D., Ph.D., head of the Division of Medical Genetics at the University of Washington in Seattle. "We have to agree on a consistent way to interpret them."

Some meeting participants stressed the need for adequate representation of diverse populations in genomic studies of diseases. James Evans, M.D., Ph.D., Bryson Distinguished Professor of Genetics and Medicine at the University of North Carolina at Chapel Hill, cited numerous reasons to include minority and medically underserved populations in genomics research, including the need to reduce health disparities and conduct good science.

"Clinically, we need to make sure advances in identifying disease-related variants get out to all populations," he said. "We also need to ensure minority participation in order for the findings to be useful because differences in variant make-up can be specific for populations with different ancestral backgrounds." 

CSER is comprised of nine research grants and an NHGRI intramural research program. Each addresses clinical and technical issues in recruiting patients, generating clinical genomic sequencing data and the social implications and psychological impact of information gleaned from genomic testing. The consortium also includes nine groups focused on understanding the ethical, legal and social complexities of returning genomic testing results to patients and families. Return of genomic testing results is not a  straightforward process, as genomic testing invariably turns up unexpected - and so-called incidental - findings.

Meeting participants concluded that the question of what to do with incidental findings continues to be a challenge. While CSER investigators and others are able to sequence genomes and entire exomes (the protein-coding portion of the genome), Dr. Rehm suggested that there may be too much recent emphasis on returning "predictive" information to doctors and patients "when our ability to predict the development of disease is so limited."

In a wrap-up session, attendees touched on a number of genomic medicine-related topics, from the role of regulatory agencies to public perception.

Dan Roden, M.D., assistant vice chancellor for personalized medicine at Vanderbilt University School of Medicine in Nashville, suggested that despite challenges associated with the use of genomic sequencing technologies, "we shouldn't lose sight of what the technology can do in medicine," particularly for difficult-to-diagnose diseases.

"The questions have shifted from 'can we integrate clinical genomics into patient care' to 'how can we do it better and what is its value,'" said Dr. Evans. "CSER is incredibly well-positioned to think hard about those challenges. We're starting to find answers to these questions now. It's an incredibly exciting time." 

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Last Updated: February 25, 2016