Fine-Mapping Chromosomal Loss at 9p21: Correlation with Prognosis in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

Senff, Nancy J.; Zoutman, Willem H.; Vermeer, Maarten H.; Assaf, Chalid; Berti, Emilio; Cerroni, Lorenzo; Espinet, Blanca; Cabrera, Ricardo Fernández de Misa; Geerts, Marie; Kempf, Werner; Mitchell, Tracey; Paulli, Marco; Petrella, Tony; Pimpinelli, Nicola; Santucci, Marco; Whittaker, Sean; Willemze, Rein; Tensen, Cornelis P.

doi:10.1038/jid.2008.357

Cited by 89 publications

(53 citation statements)

References 17 publications

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“…35,56 Recently, multiplex ligation-dependent probe amplification has been found to be a reliable tool to assess CDKN2A-CDKN2B deletion in 64 formalin-fixed cutaneous B-cell large cell lymphoma leg-type cases. 57 Finally, we observed CDKN2A-CDKN2B deletion in a high proportion of patients with advanced-stage epidermotropic CTCL. In such patients, the genetic status of the CDKN2A-CDKN2B locus had a significant prognostic impact and should be evaluated for its independent prognostic value in prospective therapeutic trials.…”

Section: Discussionmentioning

confidence: 58%

CDKN2A–CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma

et al. 2010

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Inactivation of the CDKN2A-CDKN2B locus has been reported in the most frequent subtypes of cutaneous T-cell lymphomas (CTCLs), mycosis fungoides, Sé zary syndrome (SS) and CD30 þ cutaneous anaplastic large cell lymphoma. To investigate whether genetic or epigenetic inactivation of CDKN2A-CDKN2B is more specifically observed in certain CTCL subtypes with clinical impact, we used array-comparative genomic hybridization, quantitative PCR, interphase fluorescent in situ hybridization and methylation analyses of p14 ARF p16 INK4A and p15 INK4B promoters. We studied 67 samples from 58 patients with either transformed mycosis fungoides (n ¼ 24), SS (n ¼ 16) or CD30 þ cutaneous anaplastic large cell lymphoma (n ¼ 18). We observed combined CDKN2A-CDKN2B deletion in both transformed mycosis fungoides (n ¼ 17, 71%) and SS patients (n ¼ 7, 44%), but, surprisingly, in only one CD30 þ cutaneous anaplastic large cell lymphoma case. Interphase fluorescent in situ hybridization showed 9p21 loss in 17 out of 19 cases, with 9p21 deletion indicating either hemizygous (n ¼ 4) or homozygous (n ¼ 2) deletion, with mixed patterns in most patients (n ¼ 11). The limited size of 9p21 deletion was found to account for false-negative detection by either BAC arrays (n ¼ 9) or fluorescent in situ hybridization (n ¼ 2), especially in patients with Sé zary syndrome (n ¼ 6). Methylation was found to be restricted to the p15 INK4B gene promoter in patients with or without 9p21 deletion and did not correlate with prognosis. In contrast, CDKN2A-CDKN2B genetic loss was strongly associated with a shorter survival in CTCL patients (P ¼ 0.002) and more specifically at 24 months in transformed mycosis fungoides and SS patients (P ¼ 0.02). As immunohistochemistry for p16 INK4A protein was not found to be informative, the genetic status of the CDKN2A-CDKN2B locus would be relevant in assessing patients with epidermotropic CTCLs in order to identify those cases where the disease was more aggressive. Keywords: array-based comparative genomic hybridization; cutaneous T-cell lymphoma; CDKN2A-CDKN2B; mycosis fungoides; Sé zary syndrome; 9p21 deletionThe cell cycle, and especially G1-S progression, is controlled by the p14 ARF -mdm2-p53 and p16 INK4A / p15 INK4B -Rb1 pathways (reviewed by Sharpless and DePinho 1 ). Both p16 INK4A and p15 INK4B proteins are able to induce cell-cycle arrest in the G1 phase by inhibiting the cyclin-dependent kinases CDK4-and CDK6-mediated phosphorylation of the retinoblastoma protein that is required for cell-cycle progression (reviewed by Barbacid et al 2 and Ortega et al 3 ). The p14 ARF protein mainly acts on the MDM2-p53 pathway, inducing either cell cycle arrest or apoptosis (reviewed by Sherr et al 4 and Gil and Peters 5 ).Interestingly, the p14 ARF , p16 INK4A and p15 INK4B proteins are encoded by the same CDKN2A-CDKN2B locus on the chromosomal band 9p21:

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Section: Discussionmentioning

confidence: 58%

CDKN2A–CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma

et al. 2010

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“…Inactivation of the CDKN2A region, by either deletion at chromosome 9p21.3 or promoter methylation has also been related to a poorer prognosis in primary cutaneous large B-cell lymphoma, leg type, 8,45 as also reported in activated B-cell diffuse Mutations in large B-cell lymphoma, leg type large B-cell lymphoma. 31 Only 5/23 (21.7%) cases of our series harbored CDKN2A deletion.…”

Section: Discussionmentioning

confidence: 97%

“…Such low rate may rely on the use of FISH with commercial probe for CDKN2A status investigation, which may escape small deletions detected by other methods. 8,46 Nodal-activated B-cell DLBCL hallmark is the constitutive activation of the NF-kB signaling pathway that promotes cell survival, proliferation and inhibition of apoptosis. 47 Mutations of B-cell receptor molecules (CD79A and CD79B) or of negative (TNFAIP3/A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7/TAK1, and TNFRSF11A/RANK) regulators of NF-kB 18 all contribute to NF-kB constitutive activation.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 At diagnosis, age, leg involvement, extent of skin disease, and CDKN2A (P16) inactivation have been found as predictive for progression and death. 3,[6][7][8] Contrary to nodal diffuse large B-cell lymphomas, few studies have identified molecular pathways contributing to primary cutaneous large B-cell lymphoma, leg type oncogenesis and from what stage of B-cell differentiation such lymphoma arise. In nodal diffuse large B-cell lymphomas, gene expression profiling has identified two main signatures corresponding to the differentiation stage of the cell of origin: germinal center or post-germinalcenter activated B cell.…”

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Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma

et al. 2014

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Primary cutaneous large B-cell lymphoma, leg type has been individualized from nodal diffuse large B-cell lymphoma. The objective of this study was to screen primary cutaneous large B-cell lymphoma, leg type for genetic alterations recently described in nodal diffuse large B-cell lymphoma. Skin biopsies from 23 patients were analyzed for IRF4, BCL2, BCL6, and MYC expression. FISH testing was performed for BCL2, BCL6, MYC with separation probes and for CDKN2A and PRDM1/BLIMP1 deletion. Multiple sequential FISH analyses with up to six probes were performed to define samples with multiple cytogenetic alterations. MYD88 mutations were studied by Sanger sequencing. All cases but one displayed at least one genetic alteration (96%). Nine patients exhibited a single genetic mutation and 12 combined several alterations (52%). We observed a split for BCL2, BCL6, or MYC in 1/23, 6/23, and 3/23 of cases, respectively. No double-hit lymphoma was observed. CDKN2A deletion was detected by FISH in only 5/23 cases. BLIMP1 and/or 6q deletion was observed at a higher rate in 10/20 of cases. No correlation between rearrangement and immunohistochemical expression was found for BCL2 or MYC. FISH tracking of sequential hybridizations showed that several alterations were carried by the same nuclei. The p.L265P MYD88 mutation was found in 11/18 (61%) of cases. Contrary to most cutaneous lymphomas that rarely harbor primary genetic alteration of their nodal histological equivalent, primary cutaneous large B-cell lymphoma, leg type seems to be a 'cutaneous counterpart' of activated B-cell-like diffuse large B-cell lymphoma with a similar cytogenetic profile and a high rate of MYD88 oncogenic L265P mutation. This also suggests a common lymphomagenesis with NF-jB activation, strong IRF4 expression and terminal B-cell differentiation blockage. Our data support the use of therapies targeting NF-jB, as most patients displayed disease progression and resistance to conventional therapies.

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“…Deletions that may potentially contain MIR31 have been recently reported in urothelial carcinomas (37), and down-regulation of this microRNA has been observed in gastric cancer (38). Also, 9p21.3 deletions were found in 31% of non-small lung cancers (39), ϳ85% of pancreatic adenocarcinomas (40), 35% of biliary tract tumors (41), 37.5% of osteosarcomas (42), 38% of soft tissue sarcomas (43), 75% of gliomas (44), 33-39% of T-cell acute lymphoblastic leukemias, 67% of primary cutaneous diffuse large B-cell lymphoma of the leg type (45), and ϳ17% of breast cancers (46). In a study on solid tumors that metastasize in brain, 9p21.3 loss was among four most frequent losses detected in 70% of cases (47).…”

Section: Discussionmentioning

confidence: 99%

Pro-tumorigenic Effects of miR-31 Loss in Mesothelioma

Ivanov

Goparaju

Lopez

et al. 2010

Journal of Biological Chemistry

121

113

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The human genome encodes several hundred microRNA (miRNA) genes that produce small (21-23n) single strand regulatory RNA molecules. Although abnormal expression of miRNAs has been linked to cancer progression, the mechanisms of this dysregulation are poorly understood. Malignant mesothelioma (MM) of pleura is an aggressive and highly lethal cancer resistant to conventional therapies. We and others previously linked loss of the 9p21.3 chromosome in MM with short time to tumor recurrence. In this study, we report that MM cell lines derived from patients with more aggressive disease fail to express miR-31, a microRNA recently linked with suppression of breast cancer metastases. We further demonstrate that this loss is due to homozygous deletion of the miR-31-encoding gene that resides in 9p21.3. Functional assessment of miR-31 activity revealed its ability to inhibit proliferation, migration, invasion, and clonogenicity of MM cells. Re-introduction of miR-31 suppressed the cell cycle and inhibited expression of multiple factors involved in cooperative maintenance of DNA replication and cell cycle progression, including pro-survival phosphatase PPP6C, which was previously associated with chemotherapy and radiation therapy resistance, and maintenance of chromosomal stability. PPP6C, whose mRNA is distinguished with three miR-31-binding sites in its 3-untranslated region, was consistently down-regulated by miR-31 introduction and upregulated in clinical MM specimens as compared with matched normal tissues. Taken together, our data suggest that tumorsuppressive propensity of miR-31 can be used for development of new therapies against mesothelioma and other cancers that show loss of the 9p21.3 chromosome.

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Fine-Mapping Chromosomal Loss at 9p21: Correlation with Prognosis in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

Cited by 89 publications

References 17 publications

CDKN2A–CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma

CDKN2A–CDKN2B deletion defines an aggressive subset of cutaneous T-cell lymphoma

Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma

Pro-tumorigenic Effects of miR-31 Loss in Mesothelioma

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