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. 2012 Nov 20;107(11):1840-3.
doi: 10.1038/bjc.2012.476. Epub 2012 Oct 25.

Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma

M Linnebank  1 , S Moskau, A Kowoll, A Semmler, C Bangard, M Vogt-Schaden, G Egerer, G Schackert, H Reichmann, I G H Schmidt-Wolf, H Pels, U Schlegel
Affiliations

Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma

M Linnebank et al. Br J Cancer. .

Abstract

Background: Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients.

Methods: We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol).

Results: Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis.

Conclusion: This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol.

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Figures

Figure 1
Figure 1
Human methionine metabolism. Methotrexate (MTX) inhibits DHFR, which synthesizes 5,10-CH2-FH4 from the folate pool in two subsequent steps. The RFC1 is involved in the uptake of 5,10-CH2-FH4 and MTX to tissues and organs including the CNS. 5,10-CH2-FH4 is needed for nucleic acid synthesis and, alternatively, can be reduced by MTHFR to 5-MTHF (5-CH3-FH4). Together with methylcobalamin, 5-CH3-FH4 is used by 5-MTHF-homocysteine S-methyltransferase (MTR, also called methionine synthase) to synthesise methionine. Transcobalamin 2 (Tc2) is the major transporter protein for cobalamin. Activated methionine (S-adenosylmethionine, SAM) is the methyl group donor for numerous reactions. The degradation product of SAM is S-adenosylhomocysteine (SAH), which is hydrolysed to homocysteine by SAH-hydrolase. Homocysteine can be transsulfurated to cystathionine by the vitamin B6-dependent cystathionine beta-synthase (CBS), and subsequently, via the vitamin B6-dependent cystathionine gamma-lyase (CGL), to cysteine. Cysteine is essential for glutathione synthesis. (Finkelstein, 1990).
Figure 2
Figure 2
Age, Kanrofsky performance score, Tc2 c.776C>G and overall survival. Overall survival of patients grouped by (A) age (<60=black line, ⩾60 years=broken line), (B) Karnofsky performance score (<70=broken line, ⩾70=black line) and (C) Tc2 c.776C>G genotype (CC=black line, CG=broken line, GG=grey line) is illustrated by Kaplan–Meier curves. Censored cases are indicated by upright dashes. x axis: months; y axis: proportion of patients alive.
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