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

Abstract

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 1β 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.

Clinicopathological characteristics and genomic profile of primary sinonasal tract diffuse large B cell lymphoma (DLBCL) reveals gain at 1q31 and RGS1 encoding protein; high RGS1 immunohistochemical expression associates with poor overall survival in DLBCL not otherwise specified (NOS)

“…MYC overexpression in DLBCL confers a very poor prognosis . Defects in CDKN2A are described in DLBCL and associated with chemoresistance . TP53 aberrations are negative predictors for survival of DLBCL patients .…”

Variability in DNA methylation defines novel epigenetic subgroups of DLBCL associated with different clinical outcomes

“…This appears to be a progressive oncogenic event that is more common in more aggressive DLBCLs (clusters E and F). Prior reports highlighted frequent deletion of the INK4B-ARF-INK4A locus in patients with DLBCLs 35,36,50,51 and suggested that an alternative mechanism of gene inactivation through aberrant hypermethylation also exists and cumulatively with deletions may affect between one-third and one-half of patients with DLBCLs. In addition, we demonstrated aberrant hypermethylation of CDKN1A and CDKN1B, which is a novel finding.…”

The costimulatory molecule CD70 is regulated by distinct molecular mechanisms and is associated with overall survival in diffuse large B‐cell lymphoma

“…QMPSF is a method used to detect genomic deletions or duplications based on the simultaneous amplification of short genomic fragments (patent FR0209247) (Casilli et al, ). This approach, previously validated in different haematological and non‐haematological malignancies, was performed as previously described (Jardin et al, ; Jardin et al, , ; Guney et al, ). Each sample profile was compared with the profile of paired whole blood DNA when available or with normal DNA obtained from a reactive lymph node using GeneScan 3.1.2 software (Life Technologies, Saint‐Aubin, France).…”