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Baylor to Evaluate Exome Sequencing of Childhood Brain and Solid Tumors under NHGRI Grant

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By Molika Ashford

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

Baylor College of Medicine expects to begin enrolling patients next month in a study of how whole-exome sequencing impacts medical care for childhood cancer patients.

The project, led by Sharon Plon, a BCM medical geneticist, and Will Parsons, a pediatric oncologist, will explore whether routine exome sequencing offers information above what might be discovered through standard procedures in the care of children with brain and solid tumors. It will also measure how genomic information affects the care decisions made for those who relapse.

The group also plans to test new ways of sharing results with patients' families and will evaluate how and when to best share additional or incidental genetic information with families in the clinical setting.

In December, the BCM project received a four-year, $6 million grant from the National Human Genome Research Institute under the new Clinical Sequencing Exploratory Research Project program (CSN 12/6/2011).

According to Plon, the BCM group plans to begin enrolling patients in the study in the next few months. She told Clinical Sequencing News that since Baylor is already offering clinical whole-exome sequencing through it's newly opened Whole Genome Laboratory (CSN 11/16/2011), the team expects the project to kick off rapidly. They plan to sequence tumor and germline exome DNA in a total of 300 subjects, starting with about 75 in the first year and ramping up from there.

"Clinical sequencing is getting underway," Plon said. "But at this point, it's still unclear what the impact of sequencing is, and how to do this in the most appropriate way."

She noted that the BCM group “decided to submit a pretty focused proposal [looking only at] one group of patients, while many of the other [NHGRI-funded] sites are [taking] a more diverse approach, trying to compare different types of patients.”

The team chose children with solid tumors and brain tumors "because those are the groups for which we don’t have as effective treatments, and once a child relapses there’s not necessarily a clear next level of treatment to use.”

The group is taking a "parallel track," she said, in which it plans to "look at the implications of the sequencing of germline and tumor DNA and measure the impact of both."

Plon said the group has several questions it hopes to explore through the project. Medically, the researchers have two main areas of interest, she said. The first is to establish how often whole-exome sequencing identifies a mutation that is clearly responsible for a patient's cancer.

"That’s the question I'm particularly interested in as a medical geneticist," Plon said. "Right now an oncologist sees a patient, takes family history, and decides whether to refer the patient to me, and I decide whether testing is recommended and what gene to test for … but we don't know, using this approach, how often we [might be] missing a child that actually has a cancer susceptibility gene but fell through the filters."

In light of this, "one thing we’re going to measure is how often we identify a causative gene compared to what we would have recommended in routine clinical practice," she said.

The second medical question the group hopes to answer is how often the genomic information they glean actually impacts treatment decisions for children who experience a relapse.

Plon said the group will not apply the sequencing data to initial treatment because there are "well-defined protocols" for what to do when a child is newly diagnosed with cancer and the researchers do not want to interfere with that process.

"That is not to say that five years from now, when we've all learned a lot, that sequencing won't be used to make decisions at diagnosis," she noted. Nevertheless, at this point the aim is to "maximize the safety of the patients and families and not make claims that we're going to interrupt a process that's well established."

The group will do their sequencing in house, at BCM's newly launched, CLIA-certified Whole Genome Laboratory. Plon said sequencing will begin using the lab's Illumina HiSeqs, but the sequencing platform may change through the four years of the grant, depending on how technologies develop.

"One of the advantages of the genome center at Baylor," she said, "is that they are always trying to try out new platforms and using that to inform what the clinical labs should do. So, over the course of the study, I can certainly imagine the technologies may change," she said.

As the group begins to sequence children's DNA, it will also begin to track and examine how results can best be reported to parents. On this front, the group has several goals. One, Plon said, is to develop "novel ways" to present results back to oncologists and families using, for example, technologies like tablet computers to make data more accessible and intuitive.

"Not only does [data] need to be in the medical record, but it also needs to be understandable by the oncologist and the parents," she said.

The project plans to include two separate meetings to discuss tumor and germline sequencing results — one approximately three months after diagnosis to share results related to the patient's disease, and another to explore a broader swath of genetic changes with implications for both the children and their families.

"One thing that really distinguishes all the [NHGRI] projects funded is their different populations," Plon said.

"We're a unique example of a pediatric population where the children are quite ill," while others are looking at more stable children or adults.

"We want to assess, of the different kinds of data, what really is of interest to these families and I think that answer might be quite different for our project than for an adult [group], or for children that aren't in the middle of treatment," she said.

Furthermore, since a large proportion of the college's patient population speaks Spanish, the group plans to enroll both English and Spanish speaking families in the study, and will conduct communication analysis for both languages, Plon said.

All of the NHGRI-funded projects have a three-part structure. At Baylor, Plon and Parsons are the overall principal investigators as well as the leaders of the first project, focusing on the enrollment of patients/parents in the study and assessment of the clinical impact of the genetic sequencing results.

BCM geneticists Christine Eng and Richard Gibbs lead the second project, which will work to generate whole-exome tumor and germline data at the Whole Genome Laboratory and establish innovative reporting strategies for this data.

The third project, dealing with the communication of results, is led by Laurence McCullough of the Center for Medical Ethics and Health Policy and Richard Street from the health services department.

Plon said Street's expertise in communication will be an asset as the group plans to audiotape conversations between parents and doctors in order to analyze the process of shared decision making and develop best practices for conveying complex genomic data.


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

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