By Monica Heger
The University of Michigan's Center for Translational Pathology has begun a pilot program, dubbed MiOncoSeq, to use next-generation sequencing on cancer patients to identify clinically actionable mutations that could guide treatment.
The team is using Illumina's HiSeq 2000 to do low-pass whole-genome sequencing, exome sequencing, and transcriptome sequencing, and has developed an analysis pipeline to find actionable mutations.
Earlier this month, Chandan Kumar-Sinha, a research assistant professor of pathology in Arul Chinnaiyan's lab at UMich, gave an overview of the program at the Next-Generation Sequencing and Genomic Medicine Summit in San Francisco. He also outlined early results from the pilot study, in which the team has run xenograft samples of several patients' primary tumors through the pipeline.
The group recently received institutional review board approval to begin sequencing patients, is planning to become CLIA certified, and is considering purchasing a lower-throughput machine such as the Ion Torrent PGM or the Illumina MiSeq. Longer term, the group plans to develop a sequencing-based diagnostic test.
Initially, the researchers will accept only cancer patients seen at the University of Michigan that an internal panel decides will be most likely to benefit. The sequencing of those patients will be funded through the team's university funding. Eventually, however, they hope to make the sequencing more broadly available.
Kumar-Sinha said that the comprehensive sequencing of patients will serve two main goals — to impact treatment of that particular patient and also for basic research and discovery.
"We're sequencing … tumor samples with the explicit aim of identifying what we could learn from the tumor sequences that could be translatable in the short term, in addition to what we learn for research purposes, [such as] novel mutations and novel genes," he told Clinical Sequencing News.
To have an immediate impact on treatment, Kumar-Sinha said that the team has developed an analysis pipeline that prioritizes actionable variants, including known drug targets; mutations to any of the kinases because they are potential targets; and targets for which drug trials are currently underway.
"We're focusing in on those [mutations], which are well-characterized with respect to providing treatment," he said.
Additionally, they are developing their own curated database of actionable genes.
In collaboration with MD Anderson Cancer Center, the UMich team has tested the framework on xenograft tumors of patients with prostate cancer.
One sample came from a 67-year old with castration-resistant metastatic prostate cancer who had been on four prior therapies, all of which had failed. The combination of whole-genome, exome, and transcriptome sequencing identified a number of point mutations, copy number changes, gene fusions, and changes in gene expression that could have relevance for treatment.
For instance, they identified a TMPRSS2-ERG gene fusion, a common fusion in prostate cancers that has been shown in preliminary studies to respond to PARP inhibitors. Additionally, the CPNEA-NEK11 gene fusion could also have therapeutic implications because it involves a kinase. "We don't know of any drugs yet," said Kumar-Sinha, "but it's a kinase, so it could be targetable."
The transcriptome sequencing data helped to confirm these findings by identifying "outlier expression" in both the NEK11 and ERG genes, and provided a pathway for moving forward with additional testing of therapeutic agents. It "indicates to us that we should be attacking ERG and NEK11," Kumar-Sinha said. The next step, he said, will be to test PARP inhibitors on both in vivo and on in vitro mouse xenograft models of the samples.
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In a second prostate cancer case, the team also identified a TMPRSS2-ERG gene fusion as well as overexpression of the kinase protein PLK1, thought to be oncogenic. Kumar-Sinha said that clinical trials currently exist for PLK1 inhibitors and that the UMich team has begun testing those inhibitors on a xenograft model, and "as soon as the results appear promising," they will enroll the patient in an ongoing clinical trial .
A panel of researchers, physicians, and bioethicists are helping to decide which patients would be appropriate for sequencing. Currently, the "more challenging cases" are being recommended, including cases where the diagnosis is uncertain, or the tumor is very abnormal.
The team is still figuring out how to return results to the patients, and which results to return, Kumar-Sinha noted.
"That's a question we're still debating," he said. The team is weighing the "merits of telling the patient what we know, with the problem of overinforming the patient." He added that they are also in discussions with other groups that are developing similar clinical sequencing programs.
Institutions that have begun offering clinical sequencing for cancer patients are taking different tacks. For instance, the Fox Chase Cancer Center, which is launching a clinical sequencing service this fall, will return mutations of known significance to the oncologist in a report detailing functional information about the mutations' pathway and drugs known to target those mutations (CSN 6/15/2011).
Washington University's Genome Institute, which is doing whole-genome sequencing of cancer samples for research purposes, has also begun to explore the question of clinical sequencing. The group has already experienced a case where whole-genome sequencing of a cancer sample from a deceased patient uncovered a mutation that would have relevance for the patients' siblings. Due to a "moveable firewall" that Wash U has in place for such circumstances, the researchers were able to inform those relatives of the findings (CSN 4/26/2011). The institute is now considering moving forward with whole-genome sequencing of cancer patients specifically for clinical purposes.
The University of Michigan is the latest to join the ranks of centers offering clinical sequencing, a trend that appears to be growing. Aside from Michigan and Fox Chase, the Medical College of Wisconsin offers clinical whole-genome sequencing for its pediatric patients, and Baylor College of Medicine recently launched the Pediatric Center for Personal Cancer Genomics and Therapeutics with the aim of sequencing all new patients (CSN 8/3/2011).
Additionally, Illumina offers clinical whole-genome sequencing for some cancer patients, Partners HealthCare Center plans to launch a clinical whole-genome sequencing service in 2012 (CSN 6/15/2011), and the Translational Genomics Research Institute is currently conducting a trial to explore the feasibility of using whole-genome sequencing to guide treatment of patients with rare cancers (CSN 7/13/2011).
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