Discussion

There has been great progress in our understanding of folate pharmacogenetics involved in pediatric acute lymphoblastic leukemia treatment response. Several studies have shown positive association between certain polymorphisms or haplotypes and treatment outcome. MTHFR C677T is associated with increased risk of relapse (6) while RFC A80G (24), TS 3R/3R (18), and MTHFD1 (5) are associated with decreased EFS. Associations have also been reported with treatment toxicity. Specifically, the RFC A80G polymorphism is associated with more vomiting (12) and children with TS 2R/2R have increased risk of osteonecrosis (22).

Table 3

RFC Polymorphisms Implicated in ALL Treatment Response

Table 3

RFC Polymorphisms Implicated in ALL Treatment Response

Gene

Polymorphism

Event

Case

Control

Or

95% CI

P

Ref.

RFC

ASO variant

EFS

35

l69

2.S

1.1-S.l

O.O3

(24)

RFC

SO G/A

Vomiting (NCI-CTC grade 2 or higher)

l5

3.13

1.OS1-9.O72

O.O36

(12)

RFC

SO G/A

Neurotoxicity

l4

53

NS

(7)

While these positive associations provide promising evidence that genetic variation influences ALL treatment response, many of these studies share important limitations. Many of these studies are retrospective with modest sample sizes and varied inclusion criteria. Moreover, few studies consider the impact of multiple comparisons the reported positive associations. Further advances in pediatric ALL pharmacogenetics will be made through large-scale cooperative group studies that prospectively determine both the genotype and outcome of interest and then validate these associations in subsequent trials. As data from these studies matures, host genotype information may be used to direct the clinical care of patients.

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