Molecular Characterization of 9p21 Deletions Shows a Minimal Common Deleted Region Removing CDKN2A Exon 1 and CDKN2B Exon 2 in Diffuse Large B-Cell Lymphomas

Diffuse large B cell lymphoma represent the most frequent subtype of non Hodgkin's lymphoma, accounting for 30-40% of cases. Several studies have shown that CDKN2A and CDKN2B deletions are frequent in these lymphomas. These genes encode the P14ARF, CDKN2A, and CDKN2B proteins which play a key role in the control of the G1/S transition of the cell cycle. Using array CGH and a quantitative multiplex PCR method, we have previously identified such deletions in 36% of cases at diagnosis. Using a walking strategy to approach the breakpoints of these deletions we could identify the breakpoints junction of thirteen deletions in 11 patients and of two unbalanced translocation leading to a loss of these genes. A minimal common deleted region of 22.4 kb containing exon 1 beta of CDKN2A encoding P14ARF and exon 2 of CDKN2B encoding CDKN2B was present in all cases but one. Analysis by quantitative RT PCR showed that the expression level of these genes was decreased in these patients as compared with non deleted cases and that this level was correlated with the deletion status of P14ARF, CDKN2A, and CDKN2B. Analysis of the breakpoint sequences showed that some of them were clustered within a few hundred base-pairs suggesting, even if we failed to identify any clear recombination prone sequences, that in these deletions the rearrangement results from non-random mechanisms. (C) 2011 Wiley-Liss, Inc.