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Genetic Variant Linked to Nerve-related Side Effects from Childhood ALL Treatment

NEW YORK (GenomeWeb) – A genome-wide association study published today in the Journal of the American Medical Association describes a regulatory variant that appears to dial up the risk of adverse outcomes in children with acute lymphoblastic leukemia who are treated with the anti-cancer drug vincristine.

Researchers at St. Jude Children's Research Hospital did a prospective study of children with ALL who received either 36 or 39 vincristine doses through clinical trials at St. Jude or for the Children's Oncology Group. They then considered genotype profiles in children who experienced treatment-related toxicity — specifically a nerve problem known as peripheral neuropathy — and those who didn't.

The comparison led to a variant in the promoter region of the microtubule-related gene CEP72. The minor allele of this SNP was homozygous in 50 of the children tested, the team reported, with more than half of those in the high-risk homozygous genotype group experiencing at least one instance of vincristine-associated neuropathy. In contrast, neuropathy was identified in just over one-fifth of patients who weren't homozygous for the riskier allele.

"If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anti-cancer agent," the study's senior author William Evans, a hematological malignancies researcher at St. Jude, and his colleagues wrote.

Current therapeutics can successfully treat more than 85 percent of ALL cases, the researchers explained, decreasing the death toll of this most common childhood cancer type. But cancer survival sometimes comes at the cost of painful and lifelong side effects, prompting research into the roots of treatment-related toxicity.

For instance, a subset of children treated with the widely used and highly effective microtubule-inhibiting drug vincristine develop peripheral pain, numbness, or movement problems known as peripheral neuropathies.

In an effort to track down genetic factors that might help predict or prevent such toxicities, authors of the new study followed 222 children with newly diagnosed ALL at St. Jude and 99 children treated for relapsed ALL through the COG.

Over the course of their treatment, more than 22 percent of the COG cohort and nearly 29 percent of the patients at St. Jude experienced one or more bouts of neuropathy classified in the grade 2 to grade 4 range.

When the researchers compared Affymetrix array-based genotypes in those with or without the side effect, they found that vincristine-associated neuropathy risk often coincided with the presence of two thymine alleles at a CEP72 gene promoter SNP known as rs924607.

Some 16 percent of the 321 children included in the study were homozygous for the minor allele — a situation that seemed to coincide with lower-than-usual CEP72 gene expression, according to the team's follow-up analyses.

Some 56 percent of patients with homozygous TT alleles experienced peripheral neuropathy after vincristine treatment.

The neuropathy side effect occurred in a smaller proportion of vincristine-treated childhood ALL patients who were heterozygous for the risky allele or had two copies of cytosine at that site: neuropathy occurred in just over 21 percent of those cases.

The homozygous risk variant also corresponded to higher grade neuropathies, suggesting rs924607 may provide information on both side effect risk and severity for those treated with vincristine.

Moreover, the study's authors speculated that if the homozygous variant increases sensitivity to the drugs, as they suspect, it may be possible to treat these patients with a lower dose of vincristine without compromising the antileukemic effects of vincristine, a possibility that merits assessment in future clinical trials."