An A91V SNP in the Perforin Gene Is Frequently Found in NK/T-Cell Lymphomas

Rebeca Manso,Gorka Ruiz De Garibay,Margarita Sánchez-Beato,Maria Del Mar López,Socorro María Rodríguez-Pinilla,Miguel Ángel Piris,Luis Requena,Luis Lombardia,Lydia Sánchez,Ken Mills

doi:10.1371/journal.pone.0091521

Abstract

NK/T-cell lymphoma (NKTCL) is the most frequent EBV-related NK/T-cell disease. Its clinical manifestations overlap with those of familial haemophagocytic lymphohistiocytosis (FHLH). Since PERFORIN (PRF1) mutations are present in FHLH, we analysed its role in a series of 12 nasal and 12 extranasal-NKTCLs. 12.5% of the tumours and 25% of the nasal-origin cases had the well-known g.272C>T(p.Ala91Val) pathogenic SNP, which confers a poor prognosis. Two of these cases had a double-CD4/CD8-positive immunophenotype, although no correlation was found with perforin protein expression. p53 was overexpressed in 20% of the tumoral samples, 80% of which were of extranasal origin, while none showed PRF1 SNVs. These results suggest that nasal and extranasal NKTCLs have different biological backgrounds, although this requires validation.

Highlights

Extranodal NK/T-cell lymphomas (NKTCLs) are the main group of EBV-positive neoplasms that affect TNK cells, according to the recently revised WHO classification, which includes aggressive NK cell leukaemia, chronic active EBV disease (CAEBV), severe mosquito bite allergy and hydroa vacciniforme
The p.Ala91Val single-nucleotide variations (SNVs) was present in 12.5% of all cases analysed, which is twice the percentage of cases expected for a Caucasian population (3% in heterozygosity according to http://www.ncbi.nlm.nih.gov/SNP/snp;rs = rs35947 132)
We report for the first time the presence of the g.272C.T, p.Ala91Val SNV of the PRF1 gene in NKTCLs

Summary

Introduction

Extranodal NK/T-cell lymphomas (NKTCLs) are the main group of EBV-positive neoplasms that affect TNK cells, according to the recently revised WHO classification, which includes aggressive NK cell leukaemia, chronic active EBV disease (CAEBV), severe mosquito bite allergy and hydroa vacciniforme. Most NKTCLs probably originate from mature NK cells, while a small proportion of cases, which express ab or cd TCR, appear to derive from cytotoxic Tlymphocytes (CTLs). They usually arise as tumours or destructive lesions in the nasal cavity, maxillary sinuses or palate. They can appear in other extranodal sites, such as the skin, testis, lung or gastrointestinal tract. Despite their localised presentation in most patients, NKTCL is an aggressive lymphoma associated with a median survival for advanced-stage disease of only 6–12 months. Tumoral cells usually express cytoplasmic CD3, CD2 and, less frequently, CD56, and strongly express cytotoxic markers, including TIA-1, granzyme B and perforin [2,3,4]

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Conclusion