Codeletion of CDKN2 and MTAP genes in a subset of non‐Hodgkin's lymphoma may be associated with histologic transformation from low‐grade to diffuse large‐cell lymphoma

Abstract

Identifying the various genetic alterations that contribute to lymphomagenesis is key to our improved understanding of the biological behavior of the disease. Recently, we and others have defined a tumor suppressor region on the short arm of chromosome 9 harboring a cluster of genes, including MTAP, CDKN2A (p16INK4a), and CDKN2B (p15INK4B), which is frequently deleted in a variety of tumor types. To determine whether this region is involved in a particular subset of malignant lymphomas, we have examined 16 cases of diffuse large-cell lymphoma (DLCL) (including three cases that evolved from low-grade non-Hodgkin lymphoma (NHL) (transformed DLCL)), and nine cases of low-grade NHL that had subpopulations of large cells with a diffuse growth pattern (seven follicular NHL, one chronic lymphocytic leukemia, one mycosis fungoides). Interphase fluorescence in situ hybridization was performed on these samples using a 250-kb cosmid contig (COSp16), which encompasses MTAP, CDKN2A, and CDKN2B. Six of the 16 DLCLs and one of nine low-grade NHLs had deletions of COSp16. COSp16 was homozygously deleted in four cases; two cases had hemizygous deletions, and one case had a partial homozygous deletion of the cosmid contig. Three of 13 cases of de novo DLCL, all three transformed DLCLs, and one of nine low-grade NHL had COSp16 deletions. Although the numbers are small, COSp16 deletion was associated with transformed DLCL in contrast to de novo DLCL (P < 0.04, Fisher's exact test) or low-grade NHL (P < 0.02). The COSp16 deletion was mostly submicroscopic and was not observed in association with any specific recurring cytogenetic abnormalities. These results suggest that targeted deletion of the CDKN2A region occurs in a subset of non-Hodgkin's lymphomas, and may be associated with transformed lymphomas.

Allelic genotyping reveals a hierarchy of genomic alterations in mantle cell lymphoma associated to cell proliferation

“…Inactivation of tumor suppressor genes p15 (INK4b) and p16(INK4a) has previously been shown to be involved in secondary transformations of indolent lymphoma [14], [15,17] and specifically in the blastoid variant of MCL [14,37]. Accordingly, in the present study, LOH of 9p21 was closely associated with cell proliferation but also p53 alterations (Figs.…”

Lack of Methylthioadenosine Phosphorylase Expression in Mantle Cell Lymphoma Is Associated with Shorter Survival: Implications for a Potential Targeted Therapy

“…Interestingly, 100 kb telomeric to these genes is the locus encoding for MTAP, which is codeleted with the previous genes in many solid tumors (32 -34), acute lymphoblastic leukemia (35), and high-grade malignant lymphomas (12). However, the status of this gene in MCL has not been previously examined.…”

“…Adenine is then used to generate AMP whereas 5-methylthio-D-ribose-1-phosphate is converted into methionine (14). MTAP is expressed in all normal cells and tissues, although frequently lost in different human tumors usually due to gene deletions associated with the coincident loss of the INK4a-ARF locus (12,13,15). Malignant cells lacking MTAP, and consequently having an impaired AMP and methionine salvage pathway, are completely dependent on de novo AMP synthesis and exogenous methionine supply and thus are expected to be more sensitive to chemotherapy with antimetabolites blocking this pathway, such as L-alanosine, an amino acid analogue obtained from Streptomyces alanosinicus that blocks de novo AMP synthesis from IMP via the inhibition of the adenylosuccinate synthetase activity (16,17).…”

Pathological Metabolism of Methionine in Malignant Cells Is a Potential Target for the Antitumor Therapy

“…Неспособность опухолевых клеток поддерживать достаточный уровень метилирования в безметио-ниновой среде с гомоцистеином доказывает необхо-димость в экзогенном метионине [19]. Ограничение поступления метионина в метионин-зависимые опухолевые клетки может приводить к остановке клеточного цикла в поздней фазе S/G 2 как in vitro, так и in vivo [20,21] [62], мезотелиомы [7,63], нейробластомы [64], рака поджелудочной же-лезы [65,66,67], саркомы Юинга [68], рака мочевого пузыря [54], меланомы [69], плоскоклеточного рака головы и шеи [70]. В исследованиях с большой вы-боркой частота обнаружения делеций МТАР соста-вила 22 % для рака поджелудочной железы (n = 114) [50], 11-28 % для острого лимфобластного лейкоза (n = 284 [58], n = 140 [59], n = 227 [71]), 18 % для немелкоклеточного рака легкого (n = 50) [67], 12 % для мантийноклеточной лимфомы (n = 52) [61], 67 % для мезотелиомы плевры (n = 95) [63], 8-30 % для рака поджелудочной железы (n = 300 [65], n = 73 [66]), 41 % для меланомы (n = 75) [69].…”