CODELETION OF CDKN2 AND MTAP GENES IN A SUBSET OF NON-HODGKINS-LYMPHOMA MAY BE ASSOCIATED WITH HISTOLOGIC TRANSFORMATION FROM LOW-GRADE TO DIFFUSE LARGE-CELL LYMPHOMA

Identifying the various genetic alterations that contribute to lymphom agenesis is key to our improved understanding of the biological behavi or of the disease. Recently, we and others have defined a tumor suppre ssor region on the short arm of chromosome 9 harboring a cluster of ge nes, including MTAP, CDKN2A (p16(INK4a)), and CDKN2B (P15(INK4B)), whi ch is frequently deleted in a variety of tumor types. To determine whe ther this region is involved in a particular subset of malignant lymph omas, we have examined 16 cases of diffuse large-cell lymphoma (DLCL) (including three cases that evolved from low-grade non-Hodgkin lymphom a (NHL) (transformed DLCL)), and nine cases of low-grade NHL that had subpopulations of large cells with a diffuse growth pattern (seven fol licular 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 NHL s had deletions of COSp16. COSp16 was homozygously deleted in four cas es; two cases had hemizygous deletions, and one case had a partial hom ozygous deletion of the cosmid contig. Three of 13 cases of de novo DL CL, all three transformed DLCLs, and one of nine low-grade NHL had COS p16 deletions. Although the numbers are small, COSp 16 deletion was as sociated 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 t hat targeted deletion of the CDKN2A region occurs in a subset of non-H odgkin's lymphomas, and may be associated with transformed lymphomas. (C) 1998 Wiley-Liss, Inc.