Gene variant predicts lymphoma treatment response

By Lynda Williams, Senior medwireNews Reporter

German researchers have identified a gene variant that significantly influences the outcome of methotrexate (MTX) therapy for primary central nervous system lymphoma (PCNSL).

Among a group of 68 PCNSL patients undergoing systemic and facultative intraventricular MTX-based chemotherapy, patients who were carriers of the wildtype C allele of the transcobalamin 2 gene (TCN2 c.776C>G) had significantly longer survival than those carrying the G allele.

The C allele appeared to have a gene-dose impact, the researchers say, with average overall survival of 100 months for patients with the CC genotype, versus 76 and 52 months for patients with the CG and GG genotypes, respectively.

Just two of the 20 CC genotype patients died of tumor progression. By comparison, of the 48 patients with the CG or GG genotypes, two CG and five GG genotype patients died of tumor progression, one CG patient died from therapy-associated toxicity, and there were three probable CG genotype patient deaths from tumor progression.

The six patients who did not complete treatment were evenly distributed across the genotype groups, indicating the variant was not likely to predict completion of treatment.

There was also a trend for improved Karnofsky performance score after treatment for patients carrying the C versus the G allele.

Younger age was also significantly associated with improved survival in this population, but had no impact on Karnofsky performance score before treatment, report Michael Linnebank (University Hospital Bonn, Germany) and co-authors.

As reported in the British Journal of Cancer, the researchers were investigating why a significant proportion of patients do not achieve the typical strong response to MTX.

They have previously shown that PCNSL patients with the G allele have an increased risk for neurotoxicity, as demonstrated by white matter changes on magnetic resonance imaging.

TCN2 encodes the transporter protein for cobalamin (vitamin B12) and is required for the processing of homocysteine to methionine, as well as S-adenosylmethionine for the synthesis of myelin basic protein and other components. The missense G variant has a lower affinity to cobalamin, reducing the bioavailability of cobalamin for methionine and S-adenosylmethionine synthesis.

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