Comparative Genomic Hybridization Analysis of Natural Killer Cell Lymphoma/Leukemia

Abstract

Putative natural killer (NK) cell lymphoma/leukemia is a rare group of recently characterized hematolymphoid malignancies. They are highly aggressive and frequently present in extranodal sites, including the nasal area and the upper aerodigestive system, and nonnasal areas such as the skin and the gastrointestinal tract. According to clinicopathological features, they can be classified into nasal NK cell lymphoma, nasal-type NK cell lymphoma occurring in nonnasal areas, and NK cell lymphoma/leukemia. Genetic alterations in NK cell lymphoma/leukemia are not well defined. In this study, we have performed comparative genomic hybridization (CGH) on DNA extracted from fresh or frozen tissues of 10 patients with NK cell lymphoma/leukemia. They comprised four nasal NK cell lymphomas, one nasal-type NK cell lymphoma, and five NK cell lymphomas/leukemias. CGH showed frequent deletions at 6q16-q27 (four cases), 13q14-q34 (three cases), 11q22-q25 (two cases), 17p13 (two cases), and loss of the whole chromosome X (two cases). DNA amplification was observed in a majority of the chromosomes. Five cases showed DNA gains at region 1p32-pter. Frequent DNA gains were also found in chromosomes 6p, 11q, 12q, 17q, 19p, 20q, and Xp (three cases each). Interestingly, DNA gains were more frequent in nasal/nasal-type NK cell lymphomas than NK cell lymphoma/leukemia. These genetic alterations correlated well with karyotypic features found in some of the cases. The frequent DNA losses at 6q and 13q suggest that the presence of tumor suppressor genes at these regions is important in NK cell transformation. In addition to establishing novel patterns of genomic imbalances in these rare NK cell malignancies, which may be targets for future molecular analysis, this study also provides important information on genetic alterations in NK cell lymphomas that may be useful in defining their positions in current lymphoma classification schemes, which are increasingly focusing on phenotypic and genotypic correlations.

Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki‐67 labeling index

“…10,11,13,14 Nevertheless, 6p21 amplification is unlikely to be specific for FL, since it has been also reported in 6% of diffuse large B-cell NHLs, 12 in 13% of primary gastric NHLs 25 and in 30% of NK NHL/leukemias. 26 Using probes specific for the centromeric region and the long arm of the chromosome 6, we found that one case showed a pattern highly suggestive for the presence of an isochromosome 6p. This aberration is very common in human retinoblastoma, 27 but has also been reported in approximately 1% of acute lymphoblastic leukemia 28 and Hodgkin's lymphoma 29 and in 6% of primary mediastinal 30 and gastric NHLs, 25 as well as in individual cases of follicular, 10 nodal diffuse large B-cell 31 and nasal T/NK NHLs 32 and of Waldenstrom's macroglobulinemia.…”

Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies

“…To compare our findings with previous published data, we assembled all CGH data through an extensive literature search [4][5][6][7][8][9][10][11]21 that included three studies: conventional CGH on 9 Korean patients, 4 conventional CGH on 10 Chinese patients 8 and aCGH on 27 Japanese patients. 6 We also included other reports with cytogenetics, loss of heterozygosity (LOH) and fluorescent in situ hybridization data on 15 cases of NK-cell malignancies.…”

“…Only a few studies of genome-wide alterations have been published on NK-cell malignancies [4][5][6][7][8][9][10][11] due to the rarity of this entity and the difficulty in obtaining adequate biopsy specimens. Therefore, well-characterized NK cell lines, supplemented with tumor specimens, can have an important role in the investigation of NK-cell malignancies.…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…So far, no other genetic alterations (e.g. ITK-SYK translocation [52], IRF4 rearrangements [53], abnormalities, or deletions in chromosome 6q, 7q, or 9q [54–56]) have been linked to diagnosis, complicating clinical decisions in the treatment of PTCL patients. Moreover, combined chemotherapy (CHOP; Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone; or CHOEP with Etoposide) often results initially in favorable response rates, however relapses and refractory disease are frequently observed [45,57].…”