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Inherited SNPs Influence Leukemia Treatment Response

NEW YORK (GenomeWeb News) – Inherited genetic variations can help predict how well children with acute lymphoblastic leukemia will respond to treatment, according to a new study appearing online last night in the Journal of the American Medical Association.

"Our results show the importance of surveying variations in the entire genome in normal cells from patients, since many such variations can determine the effectiveness of chemotherapy," lead author Jun Yang, a pharmaceutical sciences fellow at St. Jude Children's Research Hospital, said in a statement.

Despite the dramatic increase in pediatric ALL cure rates over the past 40 or so years — from about 10 percent in the 1960s to around 80 percent today — treatment outcomes for ALL vary from one individual to the next. Currently, doctors guide ALL treatment using clinical features such as molecular subtype, age, and cell counts. But genetic differences also seem to contribute to the variability in treatment success.

Because leukemia cells remaining in the body following ALL treatment can influence early treatment response, relapse, and overall treatment outcomes, the researchers decided to look for genetic variations related to the presence of these lingering disease cells, called minimal residual disease. Rather than looking at disease cells, though, the researchers set their sights on inherited genetic variation in germline cells.

Using Affymetrix GeneChip Human Mapping 100K and 500K sets, the researchers evaluated 476,796 germline SNPs in 318 children being treated at St. Jude's Children's Research Hospital in Memphis and 169 children being treated in the Children's Oncology Group trial about a month after starting therapy.

"This study differs from most previous investigations of gene variations linked to chemotherapy outcome because those studies focused only on the genes of the leukemic cells themselves," senior author Mary Relling, a pharmaceutical researcher at St. Jude's Children's Hospital, said in a statement. "We focused on genomic variation that is inherited and affects all cells in the body, not just the leukemic cells."

Although the treatments at St. Jude's and the Children's Oncology Group were slightly different, the researchers found 102 germline SNPs at 72 genomic loci associated with minimal residual disease in both treatment groups regardless of age, sex, ALL subtype, and so on. Of these, 21 SNPs also predicted relapse and 21 were associated with anti-leukemia drug pharmacokinetics.

Beyond the potential prognostic implications of the new study, the results seem to provide new clues about ALL biology. For instance, the researchers identified five SNPs in a gene called IL15, which codes for interleukin 15 — a protein involved in activating some immune cells and prompting them to multiply.

Previous studies suggest that relapse risk increases when leukemia cells contain more interleukin. Consistent with this IL15-leukemia link, the new study suggests certain IL15 variants may hinder ALL treatment response by altering interleukin 15 function.

"Our finding that IL15 plays such an important role in the failure of chemotherapy suggests that this gene may be a marker we could use to predict outcome of therapy," Relling said. "IL15 might also represent a new target for novel drugs that knock out its activity and improve the outcome of patients with high levels of this interleukin."

Along with IL15 variants, the authors of the new paper suggested that inherited genetic variations in general "may be factored into treatment decisions in the future by placing additional emphasis on optimizing drug delivery to overcome host genetic variation, in addition to the current emphasis on tumor genetic variation."

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