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

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. Genes Chromosomes Cancer 22:72–78, 1998. © 1998 Wiley‐Liss, Inc.

[1]  S. Ogawa,et al.  Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies. , 1996, Blood.

[2]  B. Johansson,et al.  Cytogenetic evolution patterns in non-Hodgkin's lymphoma. , 1995, Blood.

[3]  Y. Xiong,et al.  Deletion of cyclin-dependent kinase 4 inhibitor genes P15 and P16 in non-Hodgkin's lymphoma , 1995 .

[4]  Kathleen R. Cho,et al.  Frequency of homozygous deletion at p16/CDKN2 in primary human tumours , 1995, Nature Genetics.

[5]  O. Olopade,et al.  Refined mapping of genomic rearrangements involving the short arm of chromosome 9 in acute lymphoblastic leukemias and other hematologic malignancies. , 1995, Blood.

[6]  H. Koeffler,et al.  Deletions of the cyclin-dependent kinase inhibitor genes p16INK4A and p15INK4B in non-Hodgkin's lymphomas. , 1995, Blood.

[7]  O. Olopade,et al.  Construction of a 2.8-megabase yeast artificial chromosome contig and cloning of the human methylthioadenosine phosphorylase gene from the tumor suppressor region on 9p21. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[8]  F. Mandelli,et al.  Detection of homozygous deletions of the cyclin-dependent kinase 4 inhibitor (p16) gene in acute lymphoblastic leukemia and association with adverse prognostic features. , 1995, Blood.

[9]  S. Shurtleff,et al.  Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukemia. , 1995, Blood.

[10]  O. Olopade,et al.  Detection of CDKN2 deletions in tumor cell lines and primary glioma by interphase fluorescence in situ hybridization. , 1995, Cancer research.

[11]  M. Yuille,et al.  Deletions and rearrangement of CDKN2 in lymphoid malignancy. , 1995, Blood.

[12]  C. D. Edwards,et al.  Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. , 1995, Cancer research.

[13]  B. Quesnel,et al.  p16 gene homozygous deletions in acute lymphoblastic leukemia. , 1995, Blood.

[14]  R. DePinho,et al.  Inhibition of ras-induced proliferation and cellular transformation by p16INK4 , 1995, Science.

[15]  G. Gaidano,et al.  Diffuse large cell lymphomas exhibit frequent deletions in 9p21–22 and 9q31–34 regions , 1995, Genes, chromosomes & cancer.

[16]  G. Reifenberger,et al.  CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. , 1994, Cancer research.

[17]  K. Tanaka,et al.  Homozygous loss of the cyclin-dependent kinase 4-inhibitor (p16) gene in human leukemias. , 1994, Blood.

[18]  R. Sutherland,et al.  Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M H Skolnick,et al.  Localization of a putative tumor suppressor gene by using homozygous deletions in melanomas. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[20]  D. Shibata,et al.  Rearrangements of the BCL-6 Gene in Acquired Immunodeficiency Syndrome-Associated Non-Hodgkin's Lymphoma: Association With Diffuse Large-Cell Subtype , 1994 .

[21]  A. Rossi,et al.  LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients. , 1994, Blood.

[22]  D. Carson,et al.  Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers , 1994, Nature.

[23]  M. Skolnick,et al.  A cell cycle regulator potentially involved in genesis of many tumor types. , 1994, Science.

[24]  K. Offit,et al.  Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma. , 1994, Blood.

[25]  G. Hannon,et al.  A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 , 1993, Nature.

[26]  K. Offit,et al.  p53 mutations are associated with histologic transformation of follicular lymphoma. , 1993, Blood.

[27]  H. Drabkin,et al.  Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. , 1992, Blood.

[28]  R. Weinberg,et al.  Tumor suppressor genes. , 1991, Science.

[29]  C. Bloomfield,et al.  Sequential karyotypes in non‐Hodgkin lymphoma: Their nature and significance , 1990, Genes, chromosomes & cancer.

[30]  C. Osborne,et al.  An autopsy study of histologic progression in non‐Hodgkin's lymphomas 192 cases from the national cancer institute , 1983, Cancer.

[31]  C. Osborne,et al.  Histologic progression in non-Hodgkin's lymphoma. , 1982, Blood.

[32]  T. Lister,et al.  Histological transformation of non‐hodgkin's lymphoma. A prospective study , 1979, Cancer.

[33]  J. Rowley,et al.  Sequence-independent amplification and labeling of yeast artificial chromosomes for fluorescence in situ hybridization. , 1994, Cytogenetics and cell genetics.

[34]  T. Colby,et al.  Histologic conversion in the non-Hodgkin's lymphomas. , 1983, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  Iscn.  International System for Human Cytogenetic Nomenclature , 1978 .