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Dana-Farber, Broad to Evaluate Exome Sequencing of Solid Tumors as NHGRI Clinical Sequencing Center

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By Molika Ashford

This is the sixth and final installment in a series of profiles of centers awarded grants under NHGRI's Clinical Sequencing Exploratory Research Project program. We previously profiled centers at Baylor College of Medicine, the University of North Carolina, the University of Washington, Brigham and Women's Hospital, and the Children's Hospital of Philadelphia.

A team from the Dana-Farber Cancer Institute and the Broad institute has begun a study of how to best use whole-exome sequencing to inform the clinical care of patients with lung and colon tumors.

The project, led by Pasi Jänne and Levi Garraway of the Dana-Farber Cancer Institute, will sequence the exomes of at least 400 patients and work to develop best practices for how to translate genomic data into real-world treatment decisions for patients and physicians. It will also grapple with how patients receive and respond to incidental sequencing findings by giving participants the choice of whether or not to receive incidental results, and tracking patient experiences for those who opt in.

The National Human Genome Research Institute reported last month that it had granted the Dana-Farber/Broad group $6 million over four years for the study. Jänne's and Garraway's team is one of six groups funded under NHGRI's Clinical Sequencing Exploratory Research Project program, which kicked off late last year (CSN 12/6/2011).

The six projects each have a unique take on their call to investigate the technical and ethical issues of clinical sequencing. Garraway told Clinical Sequencing News that the Dana-Farber group chose to focus on whole-exome sequencing in its project because of both cost and coverage.

"We can generate a reasonably deep coverage exome for $1,000, $1,200," Garraway said. "And if you are talking about the real world of clinical specimens, no one wants to be skimping on the coverage. You want to go deep, especially, [in our case,] dealing with stromally admixed tissue.

"We thought the cost versus the yield of a whole genome was not really optimal for this kind of an exploratory study … because we know that most, though not all, of the events we might care about or could do something about now are in [things like] point mutations and chromosomal copy-number variations."

As a result, "we didn't think it was critical to have whole-genome sequencing to demonstrate the potential utility of using sequencing in this study," he said.

In its project, the Dana-Farber group plans to study at least 400 patients from the center who have solid tumors — primarily lung and colon cancer. Garraway said the Broad institute will do the sequencing and data generation using Illumina machines, and both Broad and Dana-Farber team members will review the data.

He said Broad's ability to do whole-exome sequencing on paraffin-embedded samples was an important factor in planning the project. "This allows us to enroll beyond patients with only fresh surgical material," he said. "It allows us to open up availability."

One potential concern with this approach is that the mutation spectra may change over time in patients who have recurring disease, but Garraway said the team doesn't expect this to negatively affect the study because most of the more common mutations will likely stay the same. "If patients have fresh specimens, gladly we'll take those, but we're not assuming that," he said.

More interesting than identifying mutations through exome sequencing, Garraway said, will be the work to actually make that data useful for physicians.

"When the data comes out," he said, "there will be a number of mutations, most of which we don't understand what to do with. So part of the fun of this is to figure out a framework for introducing that data."

"The top tier of information is the obvious [and more actionable] mutations like EGFR, MET amplification, that kind of thing. But below that will be a swath of information that is also potentially actionable based on literature showing these genes are linked to druggable pathways," Garraway said.

The group's task will be to create a framework for patients with these tier-two mutations. "We need to think through what might be useful to clinicians next … and how to package that data so a clinician could work with experts to actually use it in clinical care."

In addition, the team will be addressing social and psychological issues that may arise from using sequencing data in the clinic. Garraway said the group plans to survey the participating oncologists and patients on their experiences. As part of the study consent form, patients will have the chance to say 'yes' or 'no' to having access to incidental findings. If they check yes, the surveys will also assess that experience.

"We [are interested to find out] what they want to know, does it end up being helpful, does is scare more than help them?" Garraway said the team hopes patients will be "empowered without being overwhelmed."

Like the other NHGRI-funded clinical sequencing projects, the Dana-Farber effort is divided into three project areas. Jänne heads the clinical study itself, while Garraway is in charge of the sequencing and analysis arm. The third area, studying physician and patient experiences, is under the direction of co-PIs Steven Joffe and Stacey Gray.

Garraway said the team is hoping the NHGRI grant may be a seed for additional funding that could allow the project to expand either to additional cancers, or additional genomic strategies.


Have topics you'd like to see covered in Clinical Sequencing News? Contact the editor at mashford [at] genomeweb [.] com.

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