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New NHGRI Projects Seek to Further Sequencing-based Medicine

By Matt Jones

NEW YORK (GenomeWeb News) – The National Human Genome Research Institute has begun testing the waters of clinical sequencing, and five of the grants it announced Tuesday as part of its revamped Genome Sequencing Program mark its first steps toward pursuing DNA sequencing in the clinic.

These new grants do not merely fund medical sequencing studies; they aim to study how effective sequencing-based medicine can be and how it may be used ethically in support of patient care.

The $40 million that NHGRI is providing to support the new Clinical Sequencing Exploratory Research Projects will use multidisciplinary approaches involving physicians, genome researchers, ethicists, and patients and their families to conduct medical studies and to learn how genome sequencing works when the rubber hits the road in the real-world.

The central goal of this program is "to help establish how best to use genomic information in patient care," NHGRI Director Eric Green said in a press telebriefing yesterday. "This program also will study psychosocial and ethical questions related to using genomic information in clinical studies."

The new Clinical Sequencing Exploratory Research Project grants will provide $1.8 million per year to Baylor College of Medicine; $2.4 million per year to Brigham and Women's Hospital; $2.2 million per year to Children's Hospital of Philadelphia; $1.6 million per year to the University of North Carolina at Chapel Hill; and $2.3 million per year to the University of Washington.

"This is not a gene-association discovery project per se," explained Brad Ozenberger, NHGRI's program director for Genomic Medicine, who is overseeing the new initiative with Jean McEwen, who is program director for the Ethical, Legal, and Social Implications Program.

"In our history the large-scale centers have been adept at producing T's, C's, G's, and A's, and putting them together and pushing the technology and discoveries. Whereas this program is really the next step, where the actual sequencing technology, and even the disease area is less important than exploring the methods of bringing genomic sequencing into the clinic workflow and to the benefit of individual patients," Ozenberger said during the briefing.

He also said that the looking into the ethical and psychosocial implications of clinical sequencing will be an "absolutely essential" part of the program.

"As we begin to see the application of genomic sequencing into the clinic, there are many ethical questions about return of results.... When you have genetic variants of great uncertainly, how does the physician decide whether to use that information in determining treatments for the patients? And even beyond the physician's perspective is the patient's perspective," said Ozenberger.

"This is really beyond genotyping ... where you are just looking at very specific genomic variants. Here we're doing entire genome sequencing, or at least entire exome sequencing, so instead of looking at dozens of sites in the genome we may be looking at three billion sites. So, it's about how to deal with all of that unknown information, and how to act," Ozenberger explained.

At the University of North Carolina, for example, a team led by James Evans, director of the Clinical Genetics Program of the UNC Lineberger Comprehensive Cancer Center, will use whole exome sequencing on 750 UNC patients for whom there is reason to suspect that a genetic error is causing their disorders. The team will evaluate the use and performance of whole exome sequencing as a diagnostic tool, and will address the diagnostic impact of this information on the patients and their families.

"Any time you do whole exome or whole genome sequencing for somebody, you are going to find things that are potentially dynamite," Evans told GenomeWeb Daily News this week.

The UNC team wants to pursue several lines of questions, he said. "What kind of information do people really want? What is the best way of returning that information to people? Do people share with their families?" Evans said.

UNC researchers will split the participants into two groups to assess how patients deal with this genetic information — some of which will be incidental — and whether they want information about findings, such as their APoE status, which can indicate risk of Alzheimer's disease.

This particular study will focus on individuals who have cancer at young ages, those with a strong family history of cancer, and children with developmental disorders.

"It's really about trying to figure out how does this technology fit, and contribute to, medical care," Evans said.

"Everybody is excited about this new technology, and I think it is probably going to do great things, but nobody has yet figured out what really is the niche that it will fill," he added. "What is the role? Who should we sequence? How can we deal with the results in a practical, clinical way?

"I compare it to the old adage that 'when you have a hammer, everything looks like a nail.' We have this hammer of next-generation sequencing. What we're trying to do is find out what are the right nails for that," said Evans.

Researchers at UW, led by Gail Jarvik, professor of medicine and head of the Division of Medical Genetics, will study people diagnosed with colon cancer. They will use genome and exome sequencing data alongside research into ethical, legal, and social questions to find commonalities among the patients that can be applied generally to the medical, personal, family, and social issues raised by clinical genomic sequencing.

Meanwhile, scientists at the Children's Hospital of Philadelphia will conduct three studies of patients with disorders that cannot be easily diagnosed or have single-gene associations. These will include a clinical sequencing component, as well as sequencing and analysis studies, and a project that will use genetic counselors and focus groups to interview and survey parents, children, and healthcare providers about the impact and outcomes of the genetic studies.

At Baylor College of Medicine, researchers will enroll patients and parents to study the clinical impact of genetic sequencing results, will generate high-quality exome tumor data, and will pursue questions about potential ethical and social impacts of sequencing, including studies of how oncologists and patients discuss complex genomic data and its application to clinical care.

Brigham and Women's Hospital scientists will develop an informatics pipeline for interpreting patients' genetic variants and will enroll 200 patients and their doctors. Some of these patients will receive standard care, while others will receive standard care along with whole genome sequencing.

"One of the most controversial issues the study team will face is whether to look for and whether to report 'incidental' genetic findings or mutations that suggest previously unsuspected genetic predisposition to cancer," explained Robert Green, a researcher at BWH's Division of Genetics, in a statement. "Reporting too many incidental results could generate unnecessary and costly medical tests, while reporting too few could deprive patients and doctors of valuable risk information."

The Scan

Guidelines for Ancient DNA Work

More than two dozen researchers have developed new ethical guidelines for conducting ancient DNA research, which they present in Nature.

And Cleared

A UK regulator has cleared former UK Prime Minister David Cameron in concerns he should have registered as a consultant-lobbyist for his work with Illumina, according to the Financial Times.

Suit Over Allegations

The Boston Globe reports that David Sabatini, who was placed on leave from MIT after allegations of sexual harassment, is suing his accuser, the Whitehead Institute, and the institute's director.

Nature Papers on Esophageal Cancer, Origin of Modern Horses, Exome Sequencing of UK Biobank Participants

In Nature this week: genetic and environmental influences of esophageal cancer, domestic horse origin traced to Western Eurasian steppes, and more.