Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A

Møller, Michael; Kania, Per W.; Ino, Yasushi; Gerdes, Anne–Marie; Nielsen, Ole; Louis, David N.; Skjødt, Karsten; Pedersen, Niels Tinggaard

doi:10.1038/sj.leu.2401761

Cited by 58 publications

(46 citation statements)

References 44 publications

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“…This suggests a tendency for concurrent alteration of the cell cycle regulators p27, p53, and Rb or p16 in DLBCL. These findings are in keeping with previous immunohistochemical and/or molecular data that concurrent aberrations of p53 and Rb1 pathways are frequent in DLBCL, being reported in about 20 to 40% of these tumors (13,24,29,32). The concurrent disruption of growth control pathways may have implications in the cell cycle by abrogating the compensatory network that was proposed to exist between p53 and Rb1 pathways.…”

Section: Discussionsupporting

confidence: 92%

“…Group 3 is composed of simultaneous detection of low/null p27 expression, increased p53 expression, and decreased Rb or p16 expression (three alterations: 11 cases). lecular networks regulating the cell cycle in malignancies provides valuable information for the understanding of the impaired regulation of these networks and permits further insight into oncogenesis (11,15,17,19,23,24,26,29,34,36). This approach was adopted in the present study to analyze the expression of p27 in relation with components of the p53 and Rb1 growth control pathways and the status of proliferation in 80 cases of DLBCL.…”

Section: Discussionmentioning

confidence: 99%

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Low Expression of p27 Protein Combined with Altered p53 and Rb/p16 Expression Status Is Associated with Increased Expression of Cyclin A and Cyclin B1 in Diffuse Large B-Cell Lymphomas

Bai

Vlachonikolis

et al. 2001

Modern Pathology

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The expression of the cyclin-dependent kinase inhibitor (CDKI) p27 protein was investigated in relation to (1) the expression of the cell cycle regulators p53, Rb and p16 and (2) the proliferation profile as determined by the expression of Ki67, cyclin A, and cyclin B1 in 80 cases of de novo diffuse large B-cell lymphomas (DLBCL). P27 expression was low/null in large tumor cells in 58/80 cases and intermediate/high in 22/80 cases. Increased expression of p53 protein was observed in 39/80 cases. Decreased expression of Rb and p16 proteins was mutually exclusive and was observed in 5/80 and 14/80 cases, respectively. The analysis of the p27 expression status (low/null versus intermediate/high) with respect to the p53 and/or Rb/p16 expression status showed that low/null p27 expression was significantly correlated with increased p53 expression (P ‫؍‬ .018) and showed a strong trend for correlation with concurrent increased p53 expression and decreased Rb or p16 expression (P ‫؍‬ .050). These findings suggest a tendency for concurrent alterations of the cell cycle regulators p27, p53, and Rb or p16 in DLBCL, which might result in impaired tumor growth control. Indeed, the analysis of the combined p27/p53/ Rb/p16 expression status with respect to the proliferation profile showed that (1) three alterations in the combined p27/p53/Rb/p16 status (i.e., low/null P27 expression, increased expression of p53, and decreased expression of Rb or p16) were significantly correlated with increased expression of cyclin B1 (P ‫؍‬ .005) and (2) two or three alterations were significantly correlated with increased expression of cyclin A (P ‫؍‬ .014). These findings suggest combined impairment of a complex cell-cycle control network involving the CDK inhibitor p27, the P53 pathway, and the Rb1 pathway, which exerts a cooperative effect resulting in enhanced tumor cell proliferation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Low Expression of p27 Protein Combined with Altered p53 and Rb/p16 Expression Status Is Associated with Increased Expression of Cyclin A and Cyclin B1 in Diffuse Large B-Cell Lymphomas

Bai

Vlachonikolis

et al. 2001

Modern Pathology

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“…Although numerous promising cellular targets and assays have been identified, such as p53 [9,20], p16 INK4A [21], bcl-2 [22,23], bcl-6 [23,24], and gene expression profiling [25,26], none of these have gained the level of acceptance required to be routinely used for risk stratification in trials and other clinical settings. Until such biology-based markers have been validated and standardized, clinical factors will continue to be the foundation of prognosis assessment in DLBCL.…”

Section: Discussionmentioning

confidence: 99%

Factors predicting long‐term survival in low‐risk diffuse large B‐cell lymphoma

Møller¹,

Pedersen²,

Christensen³

2003

American J Hematol

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The International Prognostic Index (IPI) is widely used for risk stratification of patients with diffuse large B-cell lymphoma (DLBCL). However, even among patients with low-risk disease, according to the IPI a substantial proportion of patients ultimately succumb to their disease. Using mature population-based data from the Danish Lymphoma Group, we analyzed if prognostic clinical pretreatment factors could be identified in patients with lowrisk DLBCL. One hundred seventy-seven patients, all with a prognostic profile as favorable as possible according to the IPI and treated with anthracycline-based combination chemotherapy (92%) or loco-regional radiotherapy/surgery (8%) with curative intent were included. The median age was 50 years and 170 achieved complete remission. The median follow-up time was 11 years. Twenty-six patients relapsed, with a median time to relapse of 12.1 months. Overall survival at 5 years and 10 years was 85% and 75%, respectively. Stage II was associated with poor response to treatment (P = 0.044). In a multivariate analysis, Stage II (P = 0.001) and age >50 years (P = 0.043) were independently associated with poor outcome. Patients without these adverse factors had an excellent prognosis, with a survival at 5 and 15 years of 90% and 80%, respectively. In contrast, patients with both adverse factors had poor outcome, with survival at 5 and 15 years of 70% and 29%, respectively (P < 0.001). The present data suggest that risk stratification of DLBCL patients with a favorable IPI score can be improved by the simple use of two clinical pretreatment factors. Am. J.

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“…In this respect, several studies have reported the clinical relevance of some genetic lesions of B-DLCL, including gross rearrangements of BCL-6 and BCL-2 or alterations of tumor suppressor genes involved in RB1 and p53 pathways. 3,4,7,[19][20][21][22][23] Because some BCL-6 gene mutations have been suggested to deregulate the BCL-6 expression, 24 the presence of BCL-6 mutations may identify B-DLCL patients with possibly different biological behavior and clinical outcome. To date, however, the clinical relevance of BCL-6 mutations in B-DLCL patients has not been analyzed thoroughly.…”

Section: Introductionmentioning

confidence: 99%

Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma

et al. 2002

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Although point mutations of the 5′ noncoding regions of the BCL-6 proto-oncogene are frequently detected in B-diffuse large cell lymphoma (B-DLCL), a thorough analysis of the clinical correlation of these mutations has not been performed to date. In this study, BCL-6 mutations were examined by DNA direct sequencing in 103 patients with B-DLCL. BCL-6 mutations were found in 53/103 patients, including 38/76 treated with standard chemotherapy and 15/27 treated with autologous stem cell transplantation (ASCT) up front. The presence of BCL-6 mutations was correlated with clinical features at diagnosis and outcome. Mutated patients had a significantly higher LDH level (66% vs 38%, P Ͻ 0.05), and bulky disease (51% vs 32%, P = 0.05). In the whole series of patients BCL-6 mutations did not affect CR and OS. Patients with BCL-6 mutations tended to have a prolonged 5-years DFS and FFS compared to those without mutations (DFS 82% vs 63%, FFS 63% vs 49%). Among B-DLCL treated with standard chemotherapy, mutated patients showed a significantly improved 5-year DFS (85% vs 61%, P Ͻ 0.05) and, notably, the only four relapses observed among mutated patients occurred in less than 8 months. The multivariate regression analysis (P Ͻ 0.01) with DFS as endpoint confirmed the independent prognostic value of BCL-6 mutations. There was a trend for 5-year failurefree survival to be better for patients with BCL-6 mutations (63% vs 43%, P = 0.09). In the 27 patients treated with ASCT, BCL-6 mutations did not correlate with outcome. These results suggest that BCL-6 mutations may predict a higher chance of being free of disease in B-DLCL treated with standard chemotherapy. Larger series of patients need to be analyzed to evaluate the clinical relevance of BCL-6 mutations properly. Leukemia (2002) 16, 268-275.

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Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A

Cited by 58 publications

References 44 publications

Low Expression of p27 Protein Combined with Altered p53 and Rb/p16 Expression Status Is Associated with Increased Expression of Cyclin A and Cyclin B1 in Diffuse Large B-Cell Lymphomas

Low Expression of p27 Protein Combined with Altered p53 and Rb/p16 Expression Status Is Associated with Increased Expression of Cyclin A and Cyclin B1 in Diffuse Large B-Cell Lymphomas

Factors predicting long‐term survival in low‐risk diffuse large B‐cell lymphoma

Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma

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