Impact of TP53 mutation and 17p deletion in mantle cell lymphoma

Halldórsdóttir, Anna Margrét; Lundin, Åsa; Murray, Fiona; Mansouri, Larry; Knuutila, Sakari; Sundström, Christer; Laurell, Anna; Ehrencrona, Hans; Sander, Birgitta; Rosenquist, Richard

doi:10.1038/leu.2011.162

Cited by 91 publications

(71 citation statements)

References 15 publications

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“…14,17,18 Interestingly, both Greiner et al 18 and Halldórsdóttir et al 17 reported a median OS of 1.1 years for the TP53-mutated cases (16 and 17 patients, respectively). Here, we demonstrate for the first time that TP53 mutations are associated with poor prognosis in a homogeneously treated cohort of younger, fit patients with MCL.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16][17][18] Furthermore, del(17p13) and del(9p21) (harboring TP53 and CDKN2A, respectively) have recurrently been associated with poor outcome. 12,17,[19][20][21] Recently, Delfau-Larue et al 22 validated this in a large homogenous cohort of patients from the European-MCL Younger trial, but with no information about TP53 mutations.…”

Section: Introductionmentioning

confidence: 99%

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TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

Eskelund

Dahl

Hansen

et al. 2017

Blood

317

225

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Key Points• The intensified standard-ofcare regimens for younger patients with MCL do not overcome the deleterious effects of TP53 mutations.• MCLs with TP53 mutations should be considered for alternative frontline treatment.Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%), were significantly associated with inferior outcomes (together with MIPI, MIPI-c, blastoid morphology, and Ki67 > 30%); however, in multivariate analyses, only TP53 mutations (HR, 6.2; P < .0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P < .0001) and MIPI-c high-risk (HR, 2.6; P 5 .003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P < .0001). TP53 mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction-and high-dose chemotherapy. In conclusion, we show that TP53 mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents. (Blood. 2017;130(17):1903-1910

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

Eskelund

Dahl

Hansen

et al. 2017

Blood

317

225

View full text Add to dashboard Cite

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“…Deletions of 17p and TP53 mutations are negative prognostic markers. 28,[33][34][35][36] Recently, gene expression profiling and IHC have identified the transcription factor SOX11 as a new tumor marker in MCL, being positive in ϳ 90% of MCL cases, 21,22,37 including the rare cyclin D1 Ϫ tumors 22,23 but not in other small-cell lymphomas; B-cell chronic lymphocytic lymphoma/small cell lymphoma, marginal zone lymphoma, and follicular lymphoma. Moreover, nonmalignant lymphocytes lack SOX11 expression.…”

Section: Discussionmentioning

confidence: 99%

Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma

Nygren¹,

Wennerholm

Klimkowska³

et al. 2012

Blood

141

102

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The prognostic role of the transcription factor SOX11 in mantle cell lymphoma (MCL) is controversial. We investigated prognostic markers in a population-based cohort of 186 MCL cases. Seventeen patients (9%) did not require any therapy within the first 2 years after diagnosis and were retrospectively defined as having an indolent disease. As expected, indolent MCL had less frequent B symptoms and extensive nodal involvement and 88% of these cases expressed SOX11.In our cohort 13 cases (7.5%) lacked nuclear SOX11 at diagnosis. SOX11 ؊ MCL had a higher frequency of lymphocytosis, elevated level of lactate dehydrogenase (LDH), and p53 positivity. The overall survival in the whole cohort, excluding 37 patients receiving autologous stem cell transplantation, was 3.1 year and in patients with indolent or nonindolent disease, 5.9 and 2.8 years, respectively (P ‫؍‬ .004). SOX11 ؊ cases had a shorter overall survival, compared with SOX11 ؉ cases, 1.5 and 3.2 years, respectively (P ‫؍‬ .014). In multivariate analysis of overall survival, age > 65 (P ‫؍‬ .001), Eastern Cooperative Oncology Group score > 2 (P ‫؍‬ .022), elevated LDH level (P ‫؍‬ .001), and p53 expression (P ‫؍‬ .001) remained significant, and SOX11 lost significance. We conclude that most indolent MCLs are SOX11 ؉ and that SOX11 cannot be used for predicting an indolent disease course. (Blood. 2012;119(18): 4215-4223)

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“…54 Another protein commonly affected in tumorigenesis is p53 and disruption of the p53 pathway is a common event in MCL. TP53 is one of the most frequently mutated genes (14%-20%) in MCL patients [58][59][60] and both TP53 mutations and strong expression of the protein have been correlated to shorter survival 22,59 and high proliferation. 61 In our recent study, we explored the impact of the molecular markers Ki-67, Cyclin D1, SOX11, and p53 to add prognostic power to MIPI using multivariate analysis.…”

Section: Sox11 As a Prognostic Toolmentioning

confidence: 99%

Emerging role of SOX11 in mantle cell lymphoma

Kuci¹,

Nordström²,

Ek³

2015

BLCTT

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During recent years the neural transcription factor SOX11 has been established as an important biomarker for mantle cell lymphoma. SOX11 is both a diagnostic and prognostic antigen, and may potentially be used for treatment selection for younger patients, in relation to protocols including high dose chemotherapy. The molecular pathways involved are still not fully elucidated and, as SOX11 can interact with several co-transcription factors, functional assays need to be carefully designed to pinpoint SOX11-specific function in a defined cellular context. Furthermore, as SOX11 belongs to a large family of homologous proteins, analysis of SOX11 has been limited by the availability of specific antibodies for detection and pull-down. In this review, we discuss the emerging role of SOX11 in mantle cell lymphoma and discuss the potential impact in relation to tumorigenesis, diagnostics, prognostics, and therapy.

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Impact of TP53 mutation and 17p deletion in mantle cell lymphoma

Cited by 91 publications

References 15 publications

TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma

Emerging role of SOX11 in mantle cell lymphoma

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