Abstract

Perforin plays a key role in the cytotoxicity of NK cells and cytotoxic T lymphocytes. Genetic mutations in perforin gene (PRF1) give rise to 30–40% of cases of familial hemophagocytic lymphohistiocytosis. We recently studied two boys who had been treated for PreB ALL and subsequently developed HLH. Both showed decreased perforin expression in NK cells and were found to be heterozygous for PRF1 A91V. The functional consequences of the PRF1 A91V (resulting from C272T transition) are controversial; between 3 and 17% of apparently normal people are heterozygous for this polymorphism depending on the population studied. Recent data suggest that A91V results in conformational change that may impair processing of perforin protein to the active form, and that the polymorphism may increase susceptibility to ALL in children (

Trambas et al,
Blood
2005
;
106
:
932
;
Santoro et al,
Haematologica
2005
;
90
:
697
). We have genotyped 655 normal blood donors and 2,272 children with ALL treated on Pediatric Oncology Group 9900 clinical trials. Genotyping was performed using a specific PCR assay (Taqman). Genotypes in the normal US blood donors showed significant variation in allele frequency by race, with a very low frequency of the variant allele in black controls (0.7% compared with 4% in white controls). Allele frequencies did not vary by gender and genotype frequencies were in Hardy Weinberg equilibrium (whites C/C 92%; C/T 8%; T/T 0.2%). In light of the low frequency of the variant allele in blacks, analysis of leukemia cases was restricted to a comparison of white cases and white controls. Analyses were performed for all B-lineage ALL cases combined, and were also further stratified for known genetic subtypes of ALL.

Perforin genotype CCPerforin genotype CT or TTp-value (cases versus controls
Controls (n=507) 464 (91.5%) 43 (8.5%) 
Cases (all; n= 1321) 1198 (90.7%) 123 (9.3%) 0.58 
BCR-ABL 22 (76%) 7 (24%) 0.0048 
Trisomy 4,10 238 (93.7%) 16 (6.3%) 0.29 
TEL-AML1 250 (90.6%) 26 (9.4%) 0.66 
E2A-PBX 24 (92.3%) 2 (7.7%) 0.89 
MLL abn. 40 (87%) 6 (13%) 0.29 
Hyperdiploid 244 (92.4%) 20 (7.6%) 0.66 
Hypodiploid 8 (100%) 0 (0%) 0.40 
Perforin genotype CCPerforin genotype CT or TTp-value (cases versus controls
Controls (n=507) 464 (91.5%) 43 (8.5%) 
Cases (all; n= 1321) 1198 (90.7%) 123 (9.3%) 0.58 
BCR-ABL 22 (76%) 7 (24%) 0.0048 
Trisomy 4,10 238 (93.7%) 16 (6.3%) 0.29 
TEL-AML1 250 (90.6%) 26 (9.4%) 0.66 
E2A-PBX 24 (92.3%) 2 (7.7%) 0.89 
MLL abn. 40 (87%) 6 (13%) 0.29 
Hyperdiploid 244 (92.4%) 20 (7.6%) 0.66 
Hypodiploid 8 (100%) 0 (0%) 0.40 

Taken together, these data indicate that the A91V polymorphism is not associated with an overall increased risk of childhood ALL, in contrast to the previous report. PRF1 A91V was identified with significantly increased frequency in children with BCR-ABL positive ALL. However, this observation includes a relatively small number of cases and the potential association should be explored further, perhaps in adult ALL series in which the frequency of BCR-ABL positivity is likely to be high.

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