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Childhood Disease Sequencing Project Highlights Ethical Issues of Sequencing Patients


By Monica Heger

This story was originally posted March 9.

An initiative spearheaded by Genome Canada and the Canadian Institute of Health Research to sequence childhood disease cohorts is highlighting the ethical challenges of using sequencing to study disease in patients. The $C4.5 million project has two arms — one that will use whole-genome sequencing to study childhood cancers and metastatic tumors, and another that will use exome sequencing to study rare Mendelian diseases in children.

The team studying Mendelian diseases plans to return all sequencing results to the families, while the researchers studying pediatric cancer may or may not do so.

"A key ethical question is, when you do this next-gen whole-genome sequencing, do you return that information back to the families and patients? A part of this project is to study that question," said Poul Sorensen, Johal Chair in Childhood Cancer Research at the BC Cancer Agency, who is heading up the cancer sequencing portion of the project.

Sorensen's half of the project is funded with C$2.8 million from Genome Canada and the Canadian Institute of Health Research, and began earlier this month. He said he expected the sequencing to be done within six to nine months.

Sorensen and his team will study four different tumor types: primary and metastatic tumors from osteosarcoma and medullablastoma, and primary tumors from diffuse pontine glioma and pediatric high grade glioma, two types of difficult-to-treat brain cancers.

For the osteosarcoma and medullablastoma tumors, they will sequence DNA from the primary tumor, metastatic tumor, and normal tissue of 10 samples for each tumor type. From the two brain cancers, they will sequence primary tumor and matched normal from 15 samples for each type.

Sequencing will be done on the Illumina Genome Analyzer and HiSeq 2000. In addition, the team will do transcriptome sequencing as funding allows. Sorensen said the cancers were chosen because very little is known about them, they have limited treatment options, and they tend to be associated with poor prognosis. He also hopes that studying metastatic tumors will help shed light into the mechanisms of metastasis, of which very little is known. Studying those tumors may also have implications for metastasis in adult tumors, Sorensen said.

The project is unique in that the researchers are sequencing the tumor genomes of children for whom doctors have extensive clinical data. He said that could increase the chances of finding clinically relevant mutations, such as new drug targets, but it also raises ethical questions about whether to return all the sequence information to the families. Since the study is employing whole-genome sequencing, researchers will likely discover variants that have implications for diseases other than the particular cancer being studied, as well as variants of unknown significance. The results then would have medical implications not just for the child, but for other family members as well.

As part of the project, researchers will be studying the benefits and risks of returning the results, including surveying families about their preferences. Sorensen said that it’s possible that each case will be different, and also that researchers may return just some of the results. Even figuring out how to pose the question to families in the first place is challenging, he said.

Rare Disease

The other half of Genome Canada’s and CIHR’s initiative is to use whole-exome sequencing to study rare childhood diseases. As part of that project, researchers plan to study around 100 different diseases including neurodevelopmental disorders, blindness, neurodegenerative disorders, immunodeficiency, cancer predisposition syndromes, and disorders associated with congenital malformations.

For each disorder, researchers will sequence the genomes of between one and eight patients, depending on the size of the disease cohort, with the overall goal to uncover the disease gene.

They will be using Agilent’s in-solution SureSelect capture technology, along with sequencing on Life Technologies’ SOLiD and Illumina's HiSeq. The sequencing will be done at Canada's three science and technology innovation centers: the Center for Applied Genomics in Toronto, the Genome Sciences Center in Vancouver, and the McGill University and Genome Quebec Innovation Center in Montreal. The whole project will take about 18 months.

Kym Boycott, a medical geneticist at the Children’s Hospital of Eastern Ontario who is leading that portion of the study, said that the researchers will return all the results from the study to the families. "There was never any question about not returning the results," Boycott told Clinical Sequencing News.

"The families that are being studied have been followed by clinical geneticists for years, and it's because of them that we're doing the study," she said. Aside from results that are directly associated with the specific disease, the team will also return “incidental findings with health implications," she said.

The clinical geneticists who have been working with the patients and their families will then provide genetic counseling.

While the researchers are returning results to patients, they are not disclosing the specific diseases that they are studying in order to protect patient privacy. In many cases, said Boycott, the disease is specific to a Canadian population and named after that population, so the team is keeping the diseases undisclosed to prevent stigmatization and protect patient privacy, by not making public a list of Canadian populations with genetic diseases.

After the disease has been genetically characterized, it will be renamed based on the gene involved, and results will be published based on the new name. In addition, while some of the patients have been diagnosed, the diagnosis is a clinical description of the disease, so renaming the disease based on the genetics will help clarify that diagnosis, Boycott said.

As next-gen sequencing moves into the clinic, and more and more patients are having their whole genomes sequenced, other researchers and clinicians are also struggling with whether to share the results of that sequencing, and if so, how much of the data to share.

For instance, researchers at the Mayo Clinic and the Translational Genomics Research Institute recently sequenced the genome of a pancreatic cancer patient to determine whether sequencing could be used to guide treatment (IS 2/22/2011). In that case, the researchers will only share the results with the patient if he specifically asks for them. However, because the sequencing identified potentially actionable mutations, if a doctor uses those results to make a treatment decision, the patient would likely be told the results. Additionally, the results could also have implications for his family members.

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