Mutations of the p53 Gene as a Prognostic Factor in Aggressive B-Cell Lymphoma

Ichikawa, Atsushi; Kinoshita, Tomohiro; Watanabe, Takashi; Katō, Hirokazu; Nagai, Hirokazu; Tsushita, Keitaro; Saito, Hidehiko; Hotta, Tomomitsu

doi:10.1056/nejm199708213370804

Cited by 258 publications

(183 citation statements)

References 41 publications

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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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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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“…These results are in agreement with previous studies, which associated inactivation of the TP53 gene with clinical progression, a poor prognosis, drug resistance, and low CR rates in patients with aggressive B-cell lymphoma. 45 To summarize, the current results demonstrate that the application of high-resolution scanning of the genome has contributed to identifying new regions associated with a poor outcome in a group of patients who have high-risk DLBCL and may help in the stratification of this group of aggressive lymphomas. Accordingly, the status of 2p, 10q, and 17p should be investigated in these patients.…”

Section: Discussionmentioning

confidence: 99%

Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

Robledo¹,

Garcı́a²,

Caballero³

et al. 2009

Cancer

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BACKGROUND: Diffuse large B‐cell lymphomas (DLBCLs) are the most common type of non‐Hodgkin lymphomas. With chemotherapy and progenitor stem cell transplantation, about 60% of patients with DLBCL are long‐term survivors. The International Prognostic Index identifies patients with different outcomes. However, biologic characteristics also may help to discriminate different treatments groups. METHODS: DNA copy number changes identified by array comparative genomic hybridization (array‐CGH) were studied in 40 patients who had DLBCL with a poor prognosis and who were treated uniformly with dose‐escalated cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and intensification before high‐dose chemotherapy with autologous stem cell transplantation. RESULTS: In total, 722 copy number changes were observed (median, 5 copy number changes per patient; range, 0‐75 copy number changes per patient), with a predominance of gains. Gains on 2p16 were present only in patients who failed to achieve a complete response after escalated CHOP therapy (P < .05). In univariate analysis, gains on 2p16 and losses on 17p13 (the tumor protein p53 gene TP53 gene) were associated with a poor response to the therapy. Furthermore, age >60 years and losses on 10q23.31 (the phosphatase and tensin homolog gene PTEN) or on 17p13 were associated with short survival. In multivariate analysis, only advanced age and losses on 10q23.31 retained an adverse prognostic impact. CONCLUSIONS: Array‐CGH identified multiple regions with common copy number changes, some of which were associated with outcome in patients with DLBCL. Cancer 2009. © 2009 American Cancer Society.

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“…The regimens to which TP53 mutations predicted drug resistance included treatment with purine (pentostatin) or pyrimidine (fludarabine) analogues, as well as combination regimens containing anthracycline, cyclophosphamide, cytosine arabinoside, vincristine and/or etoposide. [18][19][20][21][22][23] Considering primary (pre-surgical) treatment of breast cancer, TP53 mutations have been associated with anthracycline and mitomycin resistance, 12,[24][25][26] but not with taxane resistance; 26,27 similarly, one study evaluating efficacy of taxanes in the adjuvant setting 28 and two studies evaluating anthracyclines and taxanes administered in concert, or sequentially, found no effect of TP53 mutation status on response. 29,30 Yet, there is evidence at variance.…”

Section: Tp53mentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Mutations of the p53 Gene as a Prognostic Factor in Aggressive B-Cell Lymphoma

Abstract: Mutations of the p53 gene are associated with a poor prognosis in patients with aggressive B-cell lymphoma.

Cited by 258 publications

References 41 publications

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

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

Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

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