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

Davies, Andrew; Lee, A M; Taylor, Claire; Clear, Andrew; Goff, Lindsey K.; Iqbal, Sameena; Heavens, Darren; Calaminici, Mariarita; Norton, A. J.; Lister, T. Andrew; Fitzgibbon, Jude

doi:10.1038/sj.leu.2403802

Cited by 54 publications

(44 citation statements)

References 53 publications

(50 reference statements)

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“…TP53 mutation status of these biopsies were included as part of a previous study. 25 Two of these patients, 4 (13344 T4C: I195T) and 22 (13129_13130 ins C frameshift) showed homozygous mutation in their t-FL biopsy. Case 9 was heterozygous for a TP53 mutation (14057 G4T: G244C) that was also detected in the corresponding FL biopsy sample.…”

Section: Mutation Studiesmentioning

confidence: 99%

“…The median age at transformation was 52 (range 27-73) years. Presentation lymph nodes were analysed in 10/26 patients ( Patients 6,7,9,12,17,19,[20][21][22][23][24][25]. The t(14;18)(q32;q21) cell lines DoHH2, RL2261 and SCI-1 were also included for analysis.…”

Section: Tissue Samplesmentioning

confidence: 99%

“…These patients formed part of a tumour panel of 29 patients reported previously and the patient numbering has been maintained. 25 Patients 3, 14 and 29 were excluded from analysis as DNA was limited. In the remaining 26 patients (median 45 years ), transformation occurred a median of 3.8 years (range 1-14.6 to years) after presentation, with patients having received a median of 3 (0-13) therapies before transformation.…”

Section: Tissue Samplesmentioning

confidence: 99%

“…Tumour protein 53 (TP53) screening of this series has been published previously. 25 PCR products were sequenced directly by use of an ABI 377 DNA sequencer (PE Applied Biosystems, Foster City, CA, USA). Unincorporated primers were removed by ultrafiltration and sequencing data analysed using DNAStar (DNAStar Inc., Madison, WI, USA).…”

Section: Mutation Analysismentioning

confidence: 99%

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Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

et al. 2007

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Single-nucleotide polymorphism (SNP) array analysis was performed using the 10K GeneChip array on a series of 26 paired follicular lymphoma (FL) and transformed-FL (t-FL) biopsies and the lymphoma cell lines SCI-1, DoHH2 and RL2261. Regions of acquired homozygosity were detected in 43/52 (83%) primary specimens with a mean of 1.7 and 3.0 aberrations in the FL and t-FL, respectively. A notable feature was the occurrence of recurring sites of acquired uniparental disomy (aUDP) on 6p, 9p, 12q and 17p in cell lines and primary samples. Homozygosity of 9p and 17p arose predominantly in t-FL and in three cases rendered the cell homozygous for a preexisting mutation of either CDKN2A or TP53. These data suggest that mutation precedes mitotic recombination, which leads to the removal of the remaining wild-type allele. In all, 18 cases exhibited abnormalities in both FL and t-FL samples. In 10 cases blocks of homozygosity were detected in FL that were absent in the subsequent t-FL sample. These differences support the notion that FL and t-FL may arise in a proportion of patients by divergence from a common malignant ancestor cell rather than by clonal evolution from an antecedent FL.

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Section: Mutation Studiesmentioning

confidence: 99%

Section: Tissue Samplesmentioning

confidence: 99%

Section: Tissue Samplesmentioning

confidence: 99%

Section: Mutation Analysismentioning

confidence: 99%

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Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

et al. 2007

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“…In this issue of the journal, Davies et al 1 evaluated the role of TP53 gene mutations in transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL). 1 FL is a distinct clinicopathological entity, accounting for 20-40% of newly diagnosed adult NHL. 2,3 It is composed of cells arranged in follicles that are morphologically and immunophenotypically similar to lymphocytes of the normal germinal center (GC), from which they are thought to originate.…”

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confidence: 99%

Higher-grade transformation of follicular lymphoma – a continuous enigma

Lossos

2005

Leukemia

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Higher-grade histological transformation is a pivotal event in the natural history of low-grade non-Hodgkin's lymphoma (NHL), typically associated with more aggressive clinical behavior and a rapidly progressive clinical course refractory to treatment and short survival. Better understanding of the pathogenesis of the higher-grade transformation might lead to the identification of new therapeutic approaches that could improve patients' outcome. In this issue of the journal, Davies et al 1 evaluated the role of TP53 gene mutations in transformation of follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL). 1 FL is a distinct clinicopathological entity, accounting for 20-40% of newly diagnosed adult NHL. 2,3 It is composed of cells arranged in follicles that are morphologically and immunophenotypically similar to lymphocytes of the normal germinal center (GC), from which they are thought to originate. Although FL are indolent malignancies with the median survival of 47-8 years, it is an incurable fatal malignancy, unless it is irradiated in stage I of the disease. Higher-grade transformation to a more aggressive DLBCL occurs in 10-60% of patients. 4 The actual risk of FL transformation increases over time with reported probability ranging from 20 to 31% at 5 years to approximately 60% at 8-10 years. [5][6][7] The high frequency of higher-grade transformation of FL, regardless of treatment, suggests that the emergence of more virulent subclone of cells, typically associated with the loss of follicular histological architecture, is inherent to the genetic nature of FL cells.Characterization of the molecular mechanisms that underlie the morphologic transformation of FL is an important goal for our understanding of this process, which might lead to the identification of potential molecular therapeutic targets, whose manipulation might alter the natural history of this malignancy. Therefore, multiple studies analyzed distinct and specific molecular alterations, cytogenetics or genome-wide changes in the expression profiles associated with higher-grade transformation (reviewed in Lossos and Levy 4 ). Classically, the analytical approach of the genetic alterations associated with the transformation consisted of simultaneous analysis of tumor specimens obtained at the time of FL diagnosis and transformation. These studies revealed that the transformation process that leads to a clinically and phenotypically similar end point is associated with diverse genetic lesions. Reported genetic abnormalities associated with histological transformation of FL include nonrandom chromosomal changes, such as gains of chromosomes 7, X and 12q, 4 accumulation of mutations in the 5 0 untranslated regulatory region of the BCL-6 gene, 8 somatic mutations of the translocated BCL-2 gene, 9 inactivation of CDKN2A and CDKN2B by deletions, mutations and hypermethylation, 10-12 c-myc gene rearrangements, 13 mutations of c-myc and alteration in the expression of its target genes, 14 alterations in the expression of p38 MAPK 15 and mutati...

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Identification of molecular targets associated with transformed diffuse large B cell lymphoma using highly purified tumor cells

et al. 2009

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Follicular lymphoma (FL) frequently transforms into the more aggressive diffuse large B cell lymphoma (DLBCL‐tr), but no protein biomarkers have been identified for predictive or early diagnosis. Gene expression analyses have identified genes changing on transformation but have failed to be reproducible in different studies, reflecting the heterogeneity within the tumor tissue and between tumor samples. Gene expression analyses on Affymetrix Human Genome U133 Plus 2.0 arrays were performed, using flow cytometry sorted tumor cells derived from FL and transformed DLBCL. To identify molecular targets associated with the transformation, subsequent immunohistochemistry (IHC) analyses of the corresponding proteins were performed. Using highly purified cells, this study identified 163 genes, which were significantly deregulated during the transformation in a majority of cases. Among the upregulated transcripts, 13 genes were selected for validation using IHC, based on the availability of commercial antibodies, and galectin‐3 and NEK2 proteins specifically identify DLBCL‐tr, when compared with FL. We demonstrate that by purifying tumor cells through cell sorting, thereby reducing the heterogeneity due to infiltrating cells, it was possible to identify distinct differences between tumor entities rather than variations due to cellular composition. Galectin‐3 and NEK2 both identified a subgroup of DLBCL‐tr, and the function of these protein markers also suggests a biological role in the transformation process. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.

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

Cited by 54 publications

References 53 publications

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

Higher-grade transformation of follicular lymphoma – a continuous enigma

Identification of molecular targets associated with transformed diffuse large B cell lymphoma using highly purified tumor cells

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