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The Genetic Deletion of 6q21 and PRDM1 and Clinical Implications in Extranodal NK/T Cell Lymphoma, Nasal Type

2015-06-10 00:01:03

BioMed Research International; Vol. 2015, pp. 1-20, 2015.


Li Liang, Zhang Zhang, Ying Wang, Lin Nong, Yalin Zheng, Linlin Qu, Bo Zhang, Ting Li



Abstract


6q21 genetic deletion has been frequently detected in extranodal NK/T cell lymphoma, nasal type (EN-NK/T-NT) and PRDM1 is considered to be candidate gene. However, direct detection of PRDM1 deletion has not been well documented. We investigated the genetic alteration of 6q21 and PRDM1 in 43 cases of EN-NK/T-NT by FISH, and in vitro cell-lines were also used to detect. PRDM1 expression was evaluated by immunohistochemistry and western blot. The correlation between genetic alteration and PRDM1 expression and the significance in clinic-pathologic were analyzed.
Heterozygous deletion of 6q21 and/or PRDM1 was observed in 24 of 43 cases (55.81%) of EN-NK/T-NT, in which 6q21 deletion was 16 cases (37.21%) while PRDM1 deletion was 19 cases (44.19%), respectively. Similarly, heterozygous co-deletion of 6q21 and PRDM1 was identified in NK92 and NKL cells. The heterozygous deletion of 6q21 and/or PRDM1 was correlated with PRDM1 expression. However, genetic deletion of 6q21 and/or PRDM1 was not correlated with clinic-pathological features of EN-NK/T-NT, while PRDM1 expression showed positive effects on the outcome of patients in an expanded cohort, as those as disease site, B symptom, and clinical stage. Thus, heterozygous deletion of 6q21 and/or PRDM1 was frequently detected in EN-NK/T-NT, and correlated with down-regulation of PRDM1 protein. But, compared to PRDM1 expression, the prognostic role of genetic deletion needs to be further evaluated in larger cohort of EN-NK/T-NT patients.



INTRODUCTION


Extranodal NK/T cell lymphoma, nasal type (EN-NK/T-NT) is featured by angiocentric and angiodestructive growth pattern characteristically correlated with progressive unrelenting ulceration and necrotic granulomatous alteration in midfacial tissues. Clinically, this lymphoma exhibits highly aggressive clinical course, poor outcome and a predilection for East Asians and Central and South Americans. Our recent investigation for 142 Northern Chinese patients with peripheral NK/T cell lymphomas revealed that EN-NK/T-NT was the most prevalent subtype (38.0%). The prognosis of EN-NK/T-NT is various, greatly depending on clinical factors, such as international prognostic index, stage, therapy modes, high proliferation rate, and primary tumour location. However, previous reports for the prognostic significance of pathologic factors are distinct even controversial. Although some putative oncogenic or molecular mechanisms have been incriminated to account for
its high aggressiveness and pathogenesis, further elucidation of the genetic aberrations and pathological prognostic factors of this disease is needed.



Conventional cytogenetic studies in EN-NK/T-NT have showed chromosomal imbalances, including deletions of 1p, 6q, 11q, 13q, 17p, and gains of 1q, 2q, 7q, 17q, 20q, and recent studies reported that the deletion of chromosome 6q21 is the most frequent aberration in NK cell neoplasm and candidate genes in the region including PRDM1, FOXO3, ATG5, AIM1, and HACE1 have been investigated. Meanwhile, the inactivation of PRDM1 has been well documented and is consequently considered to be the putative candidate gene responsible for EN-NK/T-NT. In our recent research, loss of PRDM1 expression has been identified in a group of EN-NK/T-NT patients. Nevertheless, up to date, concrete data concerning the analysis for genetic alteration of 6q21 and its putative tumor suppressor gene PRDM1 are still lacking.



In this study, we retrospectively investigated 70 cases of EN-NK/T-NT, carried out fluorescence in situ hybridization (FISH) test on formalin-fixed paraffin-embedded (FFPE) tumor specimens and NK/T lymphoma cell lines, clarified the deletion status of chromosome 6q21 and specific PRDM1 gene, and evaluated the clinical significances and prognostic factors.



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Key Words


Extranodal NK/T-cell lymphoma | Nasal type | 6q21 | PRDM1