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U Michigan to Evaluate Clinical Exome and Transcriptome Sequencing of Rare Cancers under NHGRI Grant

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This is the first in a series of profiles of centers awarded grants this year under NHGRI's Clinical Sequencing Exploratory Research program.

The University of Michigan has begun a project to sequence the exomes and transcriptomes of 400 patients with rare cancers who have failed to respond to standard treatment in order to study how such analysis can inform targeted or personalized therapy.

The project, led by Arul Chinnaiyan, joins a consortium that includes three other centers granted a total of $27 million over four years by the National Human Genome Research Institute last month under its Clinical Sequencing Exploratory Research, or CSER, program.

The four new groups — which also include the Kaiser Foundation Research Institute, the HudsonAlpha Institute for Biotechnology, and a coordinating center at the University of Washington — also join six other CSER grantees, which have been operating since early 2012 (CSN 12/7/2011).

Like the first CSER grantees, the projects are to operate as a consortium, sharing results and strategies for sequencing and analysis, and ethical practices for obtaining consent and returning results to patients and physicians.

For their first year, the four centers have been granted a total of $6.7 million. Michigan's effort is slated to receive roughly $8 million over four years overall, pending availability of funding.

Chinnaiyan told Clinical Sequencing News this week that his team at the University of Michigan has already been doing clinical cancer sequencing under a protocol dubbed Mi-OncoSeq since 2011 as a service offered to patients who have failed standard therapies and are interested in whether they could be eligible for clinical trials or off-label treatment with alternative drugs (CSN 12/19/2012).

With the CSER grant, the team is focusing more specifically on patients with advanced sarcomas or other rare cancers. Initially, Chinnaiyan said the group proposed to sequence 500 patients, but with some recent cuts to the funding, the project will most likely be limited to about 400.

Sarcomas and other rare tumors offer the group a chance to examine the potential impact of comprehensive sequencing in an area where relatively few clinical trials have been conducted, Chinnaiyan said.

"We have felt that not as much bandwidth has been applied [to these cancers] in terms of some of the more national efforts like the TCGA effort and so forth," he added. "Because of that, [we also thought] that there is more room for new discoveries in this set of patients."

Chinnaiyan said his team will continue its ongoing sequencing protocol, which relies on the Illumina HiSeq and includes whole-exome sequencing of tumor and normal DNA, as well as whole transcriptome sequencing, and, in some cases, low-pass whole-genome sequencing.

"We call it integrated sequencing," he said. "The idea, at least in the context of cancer, is to try to be comprehensive about the mutational landscape and to really capture point mutations, indels, amplifications and deletions, gene fusions, and rearrangements."

For the first 20 patients the project has enrolled so far, Chinnaiyan said the team has been able to achieve about a six-week turnaround time, from obtaining biopsies to getting results. But over the life of the project, he said he anticipates turnaround will be closer to eight weeks.

As with the previous CSER grantees, the new effort will also study the consent process, and the return of results to patients and physicians.

While the Michigan group is performing its sequencing through a CLIA certified lab, Chinnaiyan said the team is still developing a strategy for how to share results with patients and their doctors.

"We are a new grantee, so we are still figuring out exactly how that will work as part of our consortium," Chinnaiyan said. Previously, the Michigan group has presented results of its sequencing analysis to a precision medicine tumor board, founded as part of the effort's IRB-approved protocol.

According to Chinnaiyan, the board is made up of "multidisciplinary investigators, similar to a normal tumor board, but expanded to include experts in genomics, bioethics, and bioinformatics, in addition to oncologists and pathologists and radiologists."

Each patient is presented in terms of the molecular findings identified through the team's relatively comprehensive sequencing. "Based on that mutational landscape, we attempt to match [a patient] with clinical trials that might be available [or off-label therapies] if there is a mutation sensitive to a particular drug," he said.

As part of the study, the Michigan group will evaluate whether and how this approach actually identifies potential therapies or improves patient outcomes, as well as how the processes for consenting patients to receive genomic results affects them.

Chinnaiyan said that patients will be given a choice within the consent process of whether they would like to receive all potentially important results from their genome analysis or only results relevant to their cancer.

From its earlier and ongoing sequencing work, Chinnaiayan said his team has already seen some heartening evidence that the clinical sequencing strategy has a positive impact.

"Although seeing something [with therapeutic implications] is relatively rare in terms of the percentage of patients, we've certainly [had] anecdotal successes, I would say on the order of 10 to 20 percent," Chinnaiyan said. "Of course, even then there are a lot of logistical issues of actually directing [a patient] to a trial or off-label therapy, and then getting insurance to pay for it … this is something the consortium will also be looking at.

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