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St. Jude's Team Uncovers Gene Variants That May Influence Rx Metabolism in Pediatric ALL

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Researchers at the St. Jude Children's Research Hospital and the Children's Oncology Group have uncovered more than 100 genetic variations that appear to influence how pediatric patients with acute lymphoblastic leukemia metabolize chemotherapeutic agents.

The findings of the study, which appeared in the Jan. 28 issue of the Journal of the American Medical Association, suggest the variations could eventually help researchers design more effective chemotherapeutic agents for the disease, the study authors said in a statement.

To arrive at their findings, the researchers searched 476,796 inherited SNPs from 487 cases of newly diagnosed pediatric ALL. Of these individuals, 318 children were from St. Jude's and 169 were from COG.

The study uncovered 102 SNPs associated with the survival of leukemia cells after induction therapy, and is significant because it shows that "inherited genomic variation affects response to treatment in ALL," Mary Relling, chair of the Pharmaceutical Sciences department at St. Jude Children's Research Hospital and senior author of the published study, told Pharmacogenomics Reporter this week.

"Some of that variation is due to variation in blood disposition of anticancer drugs, some to variation in leukemic cell concentrations of drugs, and some probably to inherent sensitivity of the ALL blasts," she said.

According to Relling, the study authors will try to replicate their findings in a larger genome-wide association study with different types of treatments. She also said that, eventually, a genetic test could evolve from this research.

"We will use similar methods of genomic interrogation," Relling said. "There is no reason to narrow one's search if the technology is inexpensive enough to repeat full interrogations."

The Study

The current study is unique because instead of focusing on SNPs acquired by leukemia cells, as was the case with earlier studies, the researchers looked at SNPs in cells in the entire body associated with minimal residual disease, or MRD, which results in the survival of a small number of leukemic cells after initial chemotherapy treatment.

"This measurement helps clinicians identify patients whose disease is highly responsive to chemotherapy and therefore might be cured with milder and less-toxic treatment; and also shows if remission induction therapy will likely fail," the study authors said in a statement.

Of the 102 inherited genetic variations they linked to the level of residual leukemia, 21 were also associated with leukemic relapse. Meanwhile, the researchers discovered 21 variations that cause eradication of MRD and causes leukemic cells to respond better to chemotherapy.

Particularly, the researchers identified five SNPs on or near a gene called IL15, which heightened the risk of MRD in patients following induction therapy. Previous studies had shown that IL15 increases tumor resistance to certain chemotherapy drugs, causes leukemic cells to invade the central nervous system, and increases ALL recurrence.

"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 in a statement. "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."

While pediatric patients generally respond better to ALL treatments than adults, the two populations rely on different medications.

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The 21 SNPs that predicted MRD eradication in patients are also significantly associated with the pharmacokinetics of two antileukemic drugs, etoposide and methotrexate. The mechanism of these two drugs, according to researchers, is similar to many other treatments for pediatric lymphoblastic leukemia.

"In almost all cases, gene variation predicting faster elimination of the drugs from the body was associated with higher levels of MRD, suggesting that higher drug doses may be able to overcome the problem of low drug exposure related to an inherited tendency for fast drug elimination," Relling said.

In addition, researchers found 63 of the 102 SNPs to predict early response to therapy, relapse, or drug disposition.

Validation

Most of the 102 SNPs have not been previously identified as variants that impact the outcome of ALL chemotherapy. As a result, the JAMA authors must verify their findings using whole-genome approaches, Relling said.

In their study, the researchers interrogated the polymorphisms on the Affymetrix 500K and 100K Human mapping SNP chips, which are limited to a relatively small subset of the human genomic variation that exists, said Relling.

"Better chips will help to more fully interrogate the genome," she added.

The researchers also focused on the genomic variation that was common to two treatment schedules. In the future, "it will also be important to test for variation that is important for some treatment regimens but not for others," Relling said.

The JAMA study "showed that our genome-wide approach to identifying such SNPs is useful for identifying genetic variations that can be used to predict treatment outcomes," Jun Yang, a fellow in the St. Jude Department of Pharmaceutical Sciences and the paper's first author, said in a statement. "In the future, such information might help clinicians use drugs more effectively to overcome the patient's own genetic variation and reduce the chance of treatment failure."

While available treatments for pediatric ALL have cure rates exceeding 80 percent, responses to chemotherapies vary greatly between patients, with "much of this variance has been unexplained," the study researchers said in their statement.

"The newly discovered genetic variations, however, will likely give scientists a clearer understanding of why treatments fail in some [pediatric] patients with ALL, and how to predict early in treatment which children could be successfully treated with less aggressive treatment," they said.

The JAMA study received an undisclosed amount of financial support from St. Jude Children's Research Hospital, the National Institutes of Health, the National Cancer Institute, the NIH's Pharmacogenetics Research Network, CureSearch, and the American Lebanese Syrian Associated Charities.

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