Methylenetetrahydrofolate Reductase Mthfr

Methylenetetrahydrofolate reductase is an approximately 19,301 base pair gene with 11 exons and located on chromosome 1p36.3 (2). Multiple polymorphic sites have been described, with the C677T and A1298G most often studied. As expected, allele frequency data varies by ethnicity: The MTHFR C677T variant allele is present in 34% of Caucasians, 20% of Italians and Hispanics, 14% of African-Americans, and <1 % of Africans (3,4). The MTHFR A1298G allele is present in 27%-36% of Western Europeans (4).

3.1. MTHFR Studies

Two studies have reported a positive association between MTHFR polymorphisms and pediatric ALL relapse risk (Table 1). The first study by Krajinovic et al. evaluated 201 children with ALL treated with methotrexate as per Dana Farber Cancer Institute (DFCI) protocols 87-01, 91-01, or 95-01. Thus, the study demonstrated that the MHFR T677A1298 haplotype was associated with a decreased disease-free survival in multi-variate analysis. When children with either the MTHFR T677A1298 haplotype or the MTHFD1 A1958 variant also had a triple-repeat thymidylate synthase polymorphism, the correlation with decreased EFS was also significant (5). However, neither of the MTHFR polymorphisms alone was significantly associated with altered survival. These analyses did not include toxicity risks.

Aplenc et al. studied 520 patients enrolled on the CCG 1891 standard risk ALL trial for MTHFR C677T and A1298G polymorphisms. Patients with the MTHFR C677T variant allele had significantly increased risk of relapse with approximately one-third of all relapses attributable to possession of the variant allele. However, the MTHFR A1298G allele was not associated with increased risk of relapse (6). Variants in MTHFR were not associated with altered risks of toxicity or infection in this study.

While these studies did not show an association between MTHFR polymorphisms and toxicity, prior adult studies have shown a possible association between MTHFR polymorphisms and chemotherapy toxicity (9) or with MTX graft versus host disease prophylaxis in adult bone marrow transplant (10). Costea et al. recently reported that children with the MTHFR 677 CC genotype had significantly less grade 3 leukopenia when treated on DFCI ALL protocols (11). Likewise, patients with the CCND1 870 AA genotypes had significantly less grade 3 leukopenia, grade 2 thrombocytopenia, and grades 3 and 4 transaminase elevation.

Furthermore, there has been substantial interest in the relationship between homocys-teine levels, folate pathway polymorphisms, and neurotoxicity toxicity risk. Kishi et al. and Shimasaki et al. both found no association between higher homocysteine levels and MTHFR C677T genotypes (7,12). Moreover, both of these groups have also described an absence of an association between neurotoxicty and MTHFR C677T genotypes (7) or other toxicities including mucositis, transaminitis, emesis, and cytopenias with either the MTHFR C677T or RFC G80A genotypes (12). The conflicting results of these toxicity

Table 1

MTHFR Polymorphisms Implicated in ALL Treatment Response

Table 1

MTHFR Polymorphisms Implicated in ALL Treatment Response

Gene

Polymorphism

Event

Case

Control

Or

HR

95%CI

P

Ref.

MTHFR

T677A1298 haplotype

EFS

35

166

2.2

0.9-5.6

NS

(5)

MTHFD1

A1958

EFS

35

166

1.7

0.9-4.4

NS

(5)

MTHFR

T677A1298 haplotype

DFS

30

171

3.3

1.1-9.9

0.03

(5)

MTHFD1

A1958

DFS

30

171

1.6

1.8-5.8

NS

(5)

MTHFR

T677A1298 haplotype

OS

19

182

2.0

0.5-7.4

NS

(5)

MTHFD1

A1958

OS

19

182

1.9

0.4-9.0

NS

(5)

MTHFR

T677A1298 haplotype and TS triple repeat

EFS

16?

98?

9

1.9-42.8

0.006

(5)

MTHFD1

A1958 and TS triple repeat

EFS

16?

80?

8.9

1.8-44.6

0.007

(5)

MTHFR

C677T

Relapse

124

396

1.82

1.16-2.84

0.0008

(6)

MTHFR

C677T

Toxicity and infection

124

396

NS

(6)

MTHFR

A1298G

Relapse, toxicity, infection

124

396

NS

(6)

MTHFR

677C/T

Toxicity

14

53

NS

(7)

MTHFR

C677T

Secondary malignancy

15

30

1.51

0.43-5.31

NS

(8)

MTHFR

A1298G

Secondary malignancy

15

30

1.0

0.29-3.46

NS

(8)

studies underscores the need for well-designed, prospective pharmacogenetic studies to define the impact of MTHFR polymorphisms on short-term ALL treatment toxicity risk.

Studies of long-term toxicity risk and MTHFR polymorphisms are limited. Jazbec et al. tested the association between MTHFR C677T and A1298C polymorphisms and secondary malignancies in 449 patients treated with high-dose methotrexate (8). This study included 15 secondary malignancy cases and 30 controls matched for age, sex, length of follow-up and BFM protocol. In this report, neither the MTHFR C677T nor the A1298C polymorphisms were associated with an increased risk of secondary malignancy.

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