Copy number gain at 12q12-14 may be important in the transformation from follicular lymphoma to diffuse large B cell lymphoma

Hough, Rachael; Goepel, J R; Alcock, Helen E.; Hancock, Barry W.; Lorigan, Paul; Hammond, David W.

doi:10.1054/bjoc.2000.1638

Cited by 53 publications

(47 citation statements)

References 28 publications

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“…46,51,52 However, in t-FL disomy may not be the case, with CGH analysis demonstrating gains at 12q12-14 in 50% of t-FL samples. 11 Although this study confirms TP53 mutation as a contributory genetic mechanism in the process of transformation, the variable functional consequences and limited frequency suggests that targeting p53 may have only limited clinical application, instead targeting MDM2 overexpression on transformation may hold the greater promise.…”

Section: Discussionmentioning

confidence: 66%

“…48 Our observations are, however, more consistent with conventional and array-based comparative genomic hybridisation (CGH) studies of sequential FL/t-FL pairs that demonstrate only infrequent loss of 17p upon transformation. 11,13 Thus, the minority of transformation events were associated with the TP53 mutation or LOH. The alternative oncogenic mechanisms that result in phenotypic change as yet remain unclear; their elucidation hampered by limited sample availability for paired analysis.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 Transformation provides an important model for the study of oncogenesis and a number of recurring secondary events are recognised that may be of mechanistic significance. These include acquisition of recurrent chromosomal aberrations including loss of 17p and gains at 12q, [11][12][13][14] inactivation of CDKN2A and CDKN2B, 15 dysregulation of c-MYC 16,17 and translocations, 18 gains 13 and mutations involving BCL-6. [19][20][21] Despite each individual genomic insult being observed in only a subset of patients, the resulting clinical and histologic phenotypes are similar.…”

Section: Introductionmentioning

confidence: 99%

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A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma

et al. 2005

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The role of TP53 mutation in transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (t-FL) was examined in a panel of 91 lymph node biopsies derived from 29 patients pre-and post-transformation. The entire TP53 coding sequence was screened and immunocytochemistry performed to determine expression of p53 and its key regulator MDM2. A total of 10 mutations were detected in eight patients (28%), although none were present at FL diagnosis. Mutations were not detected solely at the time of transformation; in three patients, mutated TP53 arose in at least one antecedent FL sample (6 months, 2.5 years and 4 years prior to transformation). Loss of heterozygosity at the TP53 locus occurred in 2/20 informative patients (only in t-FL samples). p53 staining was positive in 82% (9/11) of available biopsies with a missense mutation, and negative in 71% (45/63) with wtTP53. MDM2 expression was significantly higher in t-FL samples (mean 72% positive; 95% confidence interval (95% CI) 68-76%) than FL (mean 58% positive; 95% CI 54-62%) (Po0.001) but did not correlate with TP53 status. TP53 mutation has only a limited role in the transformation of FL, exerting a heterogeneous influence upon phenotypic change. In contrast, dysregulation of MDM2 is frequent and may provide a more rational therapeutic target.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma

et al. 2005

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“…Interestingly, copy number gains at the 12q12-14 region, which contains the CDK2 gene, have been widely associated with human Diffuse Large BCell Lymphoma (DLBCL). [49][50][51] Deregulation of NFAT signaling pathway has been associated with different human malignancies, including lymphomas and leukemias. [52][53][54] Sustained activation of Calcineurin has been observed in both human B and T cell lymphomas, and showed intrinsic effects in the proliferation and survival of these cells, highlighting the importance of NFAT transcription factors in these malignancies.…”

Section: Discussionmentioning

confidence: 99%

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

et al. 2016

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The NFAT family of transcription factors has been primarily related to T cell development, activation, and differentiation. Further studies have shown that these ubiquitous proteins are observed in many cell types inside and outside the immune system, and are involved in several biological processes, including tumor growth, angiogenesis, and invasiveness. However, the specific role of the NFAT1 family member in naive B cell proliferation remains elusive. Here, we demonstrate that NFAT1 transcription factor controls Cyclin E expression, cell proliferation, and tumor growth in vivo. Specifically, we show that inducible expression of NFAT1 inhibits cell cycle progression, reduces colony formation, and controls tumor growth in nude mice. We also demonstrate that NFAT1-deficient naive B lymphocytes show a hyperproliferative phenotype and high levels of Cyclin E1 and E2 upon BCR stimulation when compared to wild-type B lymphocytes. NFAT1 transcription factor directly regulates Cyclin E expression in B cells, inhibiting the G1/S cell cycle phase transition. Bioinformatics analysis indicates that low levels of NFAT1 correlate with high expression of Cyclin E1 in different human cancers, including Diffuse Large B-cell Lymphomas (DLBCL). Together, our results demonstrate a repressor role for NFAT1 in cell cycle progression and Cyclin E expression in B lymphocytes, and suggest a potential function for NFAT1 protein in B cell malignancies.

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“…Amplification of the 6p21 locus, where cyclin D3 is mapped, has been previously reported by microsatellite analysis and comparative genomic hybridization in up to 7% of FLs. 10,11,13,14 Nevertheless, 6p21 amplification is unlikely to be specific for FL, since it has been also reported in 6% of diffuse large B-cell NHLs, 12 in 13% of primary gastric NHLs 25 and in 30% of NK NHL/leukemias. 26 Using probes specific for the centromeric region and the long arm of the chromosome 6, we found that one case showed a pattern highly suggestive for the presence of an isochromosome 6p.…”

Section: Discussionmentioning

confidence: 99%

Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki‐67 labeling index

Pruneri

Valentini

Fabris

et al. 2004

Intl Journal of Cancer

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An abnormal expression of cyclin D3, a key regulator of the cell cycle, has been documented in a variety of human malignancies, and the cyclin D3 gene, mapping to 6p21, may be deregulated in plasma cell myeloma and non-Hodgkin's lymphoma as a result of the t(6;14)(p21.1;q32.3) translocation and/or gene amplification. In the current study, we for the first time investigated by immunohistochemistry and fluorescence in situ hybridization (FISH) the prevalence of cyclin D3 abnormalities in follicular lymphomas (FLs), comparing the results with traditional clinicopathologic characteristics, p27 and skp2 immunoreactivity (IR) and Ki-67 labeling index (LI). Cyclin D3, skp2 and Ki-67 IR significantly increased from grade I to grade III FL (p ‫؍‬ 0.0003, p ‫؍‬ 0.0001 and p < 0.0001, respectively), while p27 IR was significantly (p < 0.0001) more prevalent in low-grade tumors. Cyclin D3 IR was directly correlated with the Ki-67 LI (p < 0.0001) and inversely correlated with p27 IR (p ‫؍‬ 0.050). None of the 13 cases analyzed by FISH showed the t(6;14) translocation, but in 2 (15.3%) grade I FLs 3 cyclin D3 signals were detected. Cohybridization with probes specific for the centromeric region and the long arm of the chromosome 6 indicated trisomy in one case and a pattern highly suggestive for the presence of an isochromosome 6p in the other case. Our data suggest that the t(6;14) translocation may be extremely uncommon in FL and that a deregulated expression of cyclin D3, possibly due to epigenetic mechanisms, may be involved in the pathogenesis of high-grade tumors.

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Copy number gain at 12q12-14 may be important in the transformation from follicular lymphoma to diffuse large B cell lymphoma

Cited by 53 publications

References 28 publications

A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma

A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki‐67 labeling index

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