Thymidylate Synthase Studies

The currently available data on the impact of 3R/3R 28 bp promoter genotype in ALL treatment response are summarized in Table 2. Krajinovic et al. evaluated 205

Table 2

TS Polymorphisms Implicated in ALL Treatment Response

Table 2

TS Polymorphisms Implicated in ALL Treatment Response

Gene

Polymorphism

Event

Case

Control

Or

HR

95%CI

P

Ref.

TS

3R/3R

Event (relapse or death)

32

173

4.8

1.1-20.3

0.04

(17)

CCND1-TS

CCND1A/CCND1A and 3R/3R

EFS

?34

171

10.7

2.9-38.7

< 0.0005

(19)

TS

3R/3R

EFS

52

192

2.5

1.3-4.8

0.005

(18)

TS

3R/3R

Relapse

40

40

1.1

0.7-2.98

NS

(21)

TS

2R/2R

Osteonecrosis

7

64

7.2

1.05-48.9

0.044

(22)

3R/3R and GSTM1 non-null

Relapse

24

246

14.5

2.46-85.2

0.031

(20)

French-Canadian children with ALL who received methotrexate 4 g/m2 as part of DFCI protocols 87-01, 91-01, or 95-01 (17). Patients homozygous for the triple repeat TS promoter polymorphism (3R/3R) had a higher risk of adverse event than children with 2R/2R homozygous or 2R/3R heterozygous alleles with an odds ratio 4.8, 95% CI 1.120.1, p = 0.04. This risk remained after correction for other known prognostic factors such as sex, age, WBC count, DNA index, and protocol (17). This finding was supported by a later study by the same group, which further examined the association between TS genotypes and EFS. This study included 259 patients with on DFCI protocols 87-01, 91-01, 95-01. and 2000-01. On univariate and multivariate analyses, the 3R allele was associated with a higher probability of reduced EFS (18).

The St. Justine group has also evaluated interactions between the 3R allele and other polymorphisms. Costea et al. reported on 205 patients genotyped for TS and cyclin D A1870G. Children with both cyclin D 1870 A/G homozygosity andTS 3R homozygosity were at increased risk of decreased event-free survival (19). Likewise, Krajinovic et al. reported that the among patients homozygous for the 3R insertion polymorphism, the absence of a 6 bp insertion in the 3'untranslated region of TS conferred a protective effect in EFS (18).

Two other groups have also evaluated the TS 28 bp insertion polymorphisms. In a subgroup analysis of the SJCRH ALL patients, Rocha et al. reported that patients with both the GSTM1 non-null genotypes and TS 3R/3R homozygosity had an increased risk of hematologic relapse (20). The German cooperative group has also evaluated the role of TS polymorphisms in ALL treatment response. In a study of 80 children on BFM protocols ALL 86 or ALL 90, Lauten et al. did not find a positive association between 3R/3R genotype and risk of relapse (21). However, the modest sample size clearly limits the statistical power in this study.

To date, one study has evaluated the role of TS polymorphisms in ALL treatment toxicity risk. Relling et al. evaluated the TS 28 bp promoter insertion as a risk factor for osteonecrosis. In this study, 64 of 297 patients who enrolled in SJCRH protocols Total XIIIB or XIV were included in the study. Twenty-five were found to have osteonecrosis on MRI and 39 did not have osteonecrosis on MRI. Children were screened according to clinical suspicion for osteonecrosis (Total XIIIB or XIV) or automatically for children age >10 years (Total XIV). Aside from age (OR 24.2, p = 0.0001, 95% CI, 4.8-122.1) and Caucasian race (OR 11.1, P = 0.037, 95% CI, 1.2-105.6), children with the TS low activity 2R/2R wild-type polymorphism were at significantly increased risk (OR 7.2, p = 0.044; 95% CI, 1.05-48.9) for osteonecrosis of the hips (22). The authors note that osteonecrosis may have been over-represented in their sample due to the study design.

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