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UW Team to Use Exome Sequencing to Diagnose Colon Cancer Patients

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By Monica Heger

This is the third in a series of profiles of centers awarded grants under the NHGRI's new Clinical Sequencing Exploratory Research program. We previously profiled centers at Brigham and Women's Hospital and the Children's Hospital of Philadelphia.

Beginning next month, researchers at the University of Washington expect to start enrolling patients with suspected familial colon cancer for a clinical trial that will compare exome sequencing's ability to yield a molecular diagnosis with the standard of care.

The project will also study many of the issues associated with using exome sequencing as a diagnostic tool, including the return of results, how patients and physicians deal with genomic data, and how that information could be incorporated into medical records.

The project is being funded under a four-year, $9.2 million grant under the National Human Genome Research Institute's new Clinical Sequencing Exploratory Research program.

Upon institutional review board approval, which is pending, a small group of patients will be enrolled in February to "make sure the whole system is running correctly," and the UW team will then scale up in March, Gail Jarvik, principal investigator of the project, told Clinical Sequencing News. In total, Jarvik said they expect to enroll just over 200 patients.

Half the patients will be assigned to receive the standard of care and the other half will be assigned to receive exome sequencing plus the standard of care.

The standard of care for diagnosing familial colon cancer is typically a "complex diagnostic pathway," Jarvik said, which results in a molecular diagnosis in only about half of the patients.

Knowing the specific genetic changes involved in colon cancer will be important for designing the best screening program to protect both the health of patients as well as family members who are currently asymptomatic, said Jarvik. Particularly for family members that share risk mutations, "additional screening is potentially life-saving." At the same time, those family members who do not have a risk mutation "can avoid costly and unpleasant testing."

The goal of incorporating exome sequencing is to test whether it can diagnose a greater number of patients and do so in a more timely fashion than current methods.

A separate group at the University of Washington has already launched a next-gen sequencing test, called ColoSeq, which sequences seven genes that are known to be involved in familial colon cancer and that are routinely sequenced with Sanger sequencing in patients thought to have familial colon cancer (CSN 12/7/2011).

The launch of this test was unrelated to the exome sequencing project, Jarvik said, but in some cases, instead of the individual gene tests the ColoSeq test may be given to patients in the standard-of-care arm of the trial.

Patients will be sequenced on the Illumina HiSeq 2000 in Deborah Nickerson's UW laboratory, which is in the midst of working through CLIA certification. Results that will be returned to the patient will first be verified with Sanger sequencing. Turnaround time will be around four weeks.

The study will also include a second wave of enrollment for patients "who we strongly believe have a genetic basis and we don't figure it out" on the first pass, said Jarvik. Those patients' family members will be invited to join the study and the team will perform either exome sequencing, or in some cases, whole-genome sequencing.

Perhaps the most complex portion of the study is figuring out how to return the results, Jarvik said. The UW team will include a large panel of physicians and medical geneticists. In addition, the team will make use of the University of Washington's large variant database, which it has compiled from numerous exome sequencing studies. Nickerson's lab has received National Institutes of Health funding for a number of large-scale exome sequencing projects, so the university has "an excellent annotation pipeline," Jarvik said.

Details for returning results have not yet been worked out, but Jarvik said the group would likely set up a tiered approach, where the colon-cancer related results are returned to the patient first.

Other medically relevant results would be returned at a separate appointment. The patient would have the opportunity to opt out of receiving some results, such as findings that might indicate a risk for an untreatable disease like Alzheimer's, or variants related to carrier status or susceptibility to certain diseases, like breast cancer — "things that have nothing to do with colon cancer," Jarvik said.

Another goal of the study is to figure out how doctors and patients view genomic information. Focus groups will be conducted with both doctors and patients, including patients who were enrolled in the study and those who were not.

Additionally, the researchers will work to figure out how the genomic data could be integrated with electronic medical records. One hindrance to incorporating the information into health records is the availability of a "very clear and medically accurate database on what are the important medical variants," Jarvik said.

"There are many variants that look like they might be disruptive because they change the charge of the amino acid, but they are hard to predict," she said.

Jarvik anticipates that at first only certain information will be included with medical records, such as pharamacogenetic variants that are well understood. Additionally, she said that she supports having the genomic information stored separately from the actual medical record, but being accessible as necessary, with the ability to import data as it becomes relevant.

That view is similar to others who are looking to link genomic data with medical records, such as Mt. Sinai Hospital in New York, which is starting a program to make genomic information from targeted sequencing tests accessible through patients' electronic medical records (CSN 12/14/2011), and the Faroe Islands, which is starting a program to sequence all 50,000 citizens (CSN 11/2/2011).

Looking ahead, Jarvik said that one of the major hurdles to adopting next-gen sequencing in the clinic would be reimbursement issues. Currently, she said that there has been some success with insurance companies covering targeted sequencing tests of up to around 20 genes.

"But, realistically, it should be cheaper to do a genome or exome at some point, rather than picking and choosing, and it certainly makes more sense than individual [gene] tests," she said.

It will be important for researchers who are doing clinical sequencing to prove that it is beneficial, she added.

"I'm a firm believer that genetics, and in particular high-throughput genetics, will play an important role in medicine," Jarvik said.


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

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