The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG-negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression

2014 ◽  
Vol 135 (6) ◽  
pp. 1399-1407 ◽  
Author(s):  
Katharina Grupp ◽  
Rebecca Boumesli ◽  
Maria Christina Tsourlakis ◽  
Christina Koop ◽  
Waldemar Wilczak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nijmegen Breakage Syndrome ◽  
Prognostic Impact ◽  
Nbs1 Gene ◽  
Pten Deletion ◽  
Prostate Cancers

scholarly journals Overexpression of the OCT-1 Gene Is a Biomarker Associated with Poor Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) - Data from a Retrospective Cohort from Latin America: Defining a Very High-Risk Clinical-Molecular Subgroup

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Luis Alberto de Padua Covas Lage ◽  
Gisele Rodrigues Gouveia ◽  
Suzete Cleusa Ferreira ◽  
Sheila Aparecida Coelho de Siqueira ◽  
Abrahão Elias Hallack Neto ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
B Cell ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Molecular Subgroup ◽  
Free Survival ◽  
Very High

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy, representing 30-40% of all non-Hodgkin's lymphomas (NHLs). They comprise a group of aggressive and heterogeneous neoplasms in terms of clinical presentation, response to therapy and prognosis. The OCT-1 gene is a member of the homodomain-POU family of transcriptional regulators of B-lymphoid differentiation. OCT-1 acts by controlling the expression of specific B-cell genes, such as BCL-2, a potent inhibitor of apoptosis that is essential for the differentiation of B-cells in the germinal center. These genes can be expressed in DLBCL, but the role of BCL-2 in its prognosis has been contradictory and the prognostic impact of the OCT-1 gene has not yet been tested in this lymphoma. Methods: In this observational, retrospective, single-center study, we investigated the prognostic impact of BCL-2 and OCT-1 gene expression in Brazilian patients with DLCBL treated with immunopolychemotherapy R-CHOP in a real-world context. The BCL-2 and OCT-1 genes were assessed in 78.5% (77/98) DLBCL patients, and the RNA for quantitative real-time PCR (qRT-PCR) was isolated from formalin-fixed and paraffin-embedded (FFPE) samples. The values obtained for gene expression were transformed into categorical variables according to their medians (6.27 for BCL-2 and 24.5 for OCT-1). The association between clinical and laboratory variables and results of gene expression was verified by the Fischer test. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariate analysis was performed using Cox's bivariate regression method and multivariate analysis using Cox multiple regression methodology. Results: The median age of the cohort was 54.5 years (15-84), 50% (49/98) were male, 49.4% (38/77) and 51.4% (40/77) showed expression of OCT-1 and BCL- 2 ≥ median, respectively. The clinical characteristics of the 98 Brazilian patients with DLBCL that comprised our cohort are summarized in Table 1. The overall response rate (ORR) in all patients was 68.4% (67/98), 65.3% (64/98) showed a complete response (CR), and 3.1% (3/98) showed partial response (PR), while 6.1% (6/98) were primary refractory. With a median follow-up of 3.77 years (95% CI: 3.2-4.1), the median overall survival (OS) was 5.43 years (95% CI: 2.2-NR) and the median progression-free survival (PFS) was 5.15 years (95% CI: 2.9-NR). The 5-year OS and PFS was 54.2% (42.2% -64.8%) and 52.0% (40.1-62.6%), respectively. In the univariate analysis OCT-1 ≥ median was associated with shortened OS (HR: 2.45, 95% CI: 1.21-4.96, p = 0.013) and PFS (HR: 2.27, 95% CI: 1.14-4.51, p = 0.019). Overexpression of BCL-2 was associated with worse PFS (HR: 2.00, 95% CI: 1.02-3.95, p = 0.043). Subgroup analysis showed that OCT-1 overexpression predominated in elderly individuals (≥ 60 years) in a statistically significant mode (29/38 cases - 76.3%, p = 0.029). It was also observed that overexpression of OCT-1 was associated with worse OS in the high-risk adjusted International Prognostic Index (aIPI) subgroup (p = 0.048) - Figure 1, and worse PFS in patients ≥ 60 years old (p = 0.025) - Figure 2. In the multivariate analysis, overexpression of OCT-1 was associated with poor PFS (HR: 2.22, 95% CI: 1.06-4.76, p = 0.035). Conclusion: In this study, we demonstrated that overexpression of the OCT-1 gene was an independent prognostic factor associated with adverse outcomes in Brazilian patients with DLCBL. We also show that in patients with unfavorable risk, such as the elderly and those with intermediate-high and high-risk IPI, overexpression of OCT-1 contributed to the identification of a very high-risk clinical-molecular subgroup, where the results with standard R-CHOP therapy are unsatisfactory, and they may benefit from intensified therapeutic strategies. Our results are preliminary and need to be validated in subsequent studies of prospective nature and with an expanded sample. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Clinical Features and Prognostic Impact of PRDM16 gene Expression in Adult Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5228-5228
Author(s):  
Genki Yamato ◽  
Hiroki Yamaguchi ◽  
Hiroshi Handa ◽  
Norio Shiba ◽  
Satoshi Wakita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Pediatric Aml ◽  
Prdm16 Gene ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a complex disease caused by various genetic alterations. Some prognosis-associated cytogenetic aberrations or gene mutations such as FLT3-internal tandem duplication (ITD), t(8;21)(q22;q22)/RUNX1-RUNX1T1, and inv(16)(p13q22)/CBFB-MYH11 have been found and used to stratify the risk. Numerous gene mutations have been implicated in the pathogenesis of AML, including mutations of DNMT3A, IDH1/2, TET2 and EZH2 in addition to RAS, KIT, NPM1, CEBPA and FLT3in the recent development of massively parallel sequencing technologies. However, even after incorporating these molecular markers, the prognosis is unclear in a subset of AML patients. Recently, NUP98-NSD1 fusion gene was identified as a poor prognostic factor for AML. We have reported that all pediatric AML patients with NUP98-NSD1 fusion showed high expression of the PR domain containing 16 (PRDM16; also known as MEL1) gene, which is a zinc finger transcription factor located near the breakpoint at 1p36. PRDM16 is highly homologous to MDS1/EVI1, which is an alternatively spliced transcript of EVI1. Furthermore, PRDM16 is essential for hematopoietic stem cell maintenance and remarkable as a candidate gene to induce leukemogenesis. Recent reports revealed that high PRDM16 expression was a significant marker to predict poor prognosis in pediatric AML. However, the significance of PRDM16 expression is unclear in adult AML patients. Methods A total of 151 adult AML patients (136 patients with de novo AML and 15 patients with relapsed AML) were analyzed. They were referred to our institution between 2004 and 2015 and our collaborating center between 1996 and 2013. The median length of follow-up for censored patients was 30.6 months. Quantitative RT-PCR analysis was performed using the 7900HT Fast Real Time PCR System with TaqMan Gene Expression Master Mix and TaqMan Gene Expression Assay. In addition to PRDM16, ABL1 was also evaluated as a control gene. We investigated the correlations between PRDM16 gene expression and other genetic alterations, such as FLT3-ITD, NPM1, and DNMT3A, and clarified the prognostic impact of PRDM16 expression in adult AML patients. Mutation analyses were performed by direct sequence analysis, Mutation Biased PCR, and the next-generation sequencer Ion PGM. Results PRDM16 overexpression was identified in 29% (44/151) of adult AML patients. High PRDM16 expression correlated with higher white blood cell counts in peripheral blood and higher blast ratio in bone marrow at diagnosis; higher coincidence of mutation in NPM1 (P = 0.003) and DNMT3A (P = 0.009); and lower coincidence of t(8;21) (P = 0.010), low-risk group (P = 0.008), and mutation in BCOR (P = 0.049). Conversely, there were no significant differences in age at diagnosis and sex distribution. Patients with high PRDM16 expression tended to be low frequency in M2 (P = 0.081) subtype, and the remaining subtype had no significant differences between high and low PRDM16 expression. Remarkably, PRDM16 overexpression patients were frequently observed in non-complete remission (55.8% vs. 26.3%, P = 0.001). Patients with high PRDM16 expression tended to have a cumulative incidence of FLT3-ITD (37% vs. 21%, P = 0.089) and MLL-PTD (15% vs. 5%, P = 0.121). We analyzed the prognosis of 139 patients who were traceable. The overall survival (OS) and median survival time (MST) of patients with high PRDM16 expression were significantly worse than those of patients with low expression (5-year OS, 17% vs. 32%; MST, 287 days vs. 673 days; P = 0.004). This trend was also significant among patients aged <65 years (5-year OS, 25% vs. 48%; MST, 361 days vs. 1565 days, P = 0.013). Moreover, high PRDM16 expression was a significant prognostic factor for FLT3-ITD negative patients aged < 65 years in the intermediate cytogenetic risk group (5-year OS, 29% vs. 58%; MST, 215 days vs. undefined; P = 0.032). Conclusions We investigated the correlations among PRDM16 expression, clinical features, and other genetic alterations to reveal clinical and prognostic significance. High PRDM16 expression was independently associated with non-CR and adverse outcomes in adult AML patients, as well as pediatric AML patients. Our finding indicated that the same pathogenesis may exist in both adult and pediatric AML patients with respect to PRDM16 expression, and measuring PRDM16 expression was a powerful tool to predict the prognosis of adult AML patients. Disclosures Inokuchi: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

scholarly journals Apoptosis Associated with Deregulated E2F Activity Is Dependent on E2F1 and Atm/Nbs1/Chk2

2004 ◽  
Vol 24 (7) ◽  
pp. 2968-2977 ◽  
Author(s):  
Harry A. Rogoff ◽  
Mary T. Pickering ◽  
Fiona M. Frame ◽  
Michelle E. Debatis ◽  
Yolanda Sanchez ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Cellular Proliferation ◽  
Normal Development ◽  
Growth Control ◽  
Nijmegen Breakage Syndrome ◽  
Gene Products ◽  
Apoptosis Induction ◽  
Human Papillomavirus Type 16 ◽  
Nbs1 Gene ◽  
Damage Response

ABSTRACT The retinoblastoma protein (Rb)/E2F pathway links cellular proliferation control to apoptosis and is critical for normal development and cancer prevention. Here we define a transcription-mediated pathway in which deregulation of E2F1 by ectopic E2F expression or Rb inactivation by E7 of human papillomavirus type 16 signals apoptosis by inducing the expression of Chk2, a component of the DNA damage response. E2F1- and E7-mediated apoptosis are compromised in cells from patients with the related disorders ataxia telangiectasia and Nijmegen breakage syndrome lacking functional Atm and Nbs1 gene products, respectively. Both Atm and Nbs1 contribute to Chk2 activation and p53 phosphorylation following deregulation of normal Rb growth control. E2F2, a related E2F family member that does not induce apoptosis, also activates Atm, resulting in phosphorylation of p53. However, we found that the key commitment step in apoptosis induction is the ability of E2F1, and not E2F2, to upregulate Chk2 expression. Our results suggest that E2F1 plays a central role in signaling disturbances in the Rb growth control pathway and, by upregulation of Chk2, may sensitize cells to undergo apoptosis.

scholarly journals Global Gene Expression Characterization of Circulating Tumor Cells in Metastasic Castration-Resistant Prostate Cancer Patients

2020 ◽  
Vol 9 (7) ◽  
pp. 2066
Author(s):  
Luis León-Mateos ◽  
Alicia Abalo ◽  
Helena Casas ◽  
Urbano Anido ◽  
Óscar Rapado-González ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Global Gene Expression ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Viable Solution ◽  
Prostate Cancers ◽  
Expression Characterization

Background: Current therapeutic options in the course of metastatic castration-resistant prostate cancers (mCRPC) reinforce the need for reliable tools to characterize the tumor in a dynamic way. Circulating tumor cells (CTCs) have emerged as a viable solution to the problem, whereby patients with a variety of solid tumors, including PC, often do not have recent tumor tissue available for analysis. The biomarker characterization in CTCs could provide insights into the current state of the disease and an overall picture of the intra-tumor heterogeneity. Methods: in the present study, we applied a global gene expression characterization of the CTC population from mCRPC (n = 9), with the goal to better understand the biology of these cells and identify the relevant molecules favoring this tumor progression. Results: This analysis allowed the identification of 50 genes specifically expressed in CTCs from patients. Six of these markers (HOXB13, QKI, MAOA, MOSPD1, SDK1, and FGD4), were validated in a cohort of 28 mCRPC, showing clinical interest for the management of these patients. Of note, the activity of this CTC signature was related to the regulation of MYC, a gene strongly implicated in the biology of mCRPC. Conclusions: Overall, our results represent new evidence on the great value of CTCs as a non-invasive biopsy to characterize PC.

Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4836-4843 ◽  
Author(s):  
Gonzalo Gutiérrez-García ◽  
Teresa Cardesa-Salzmann ◽  
Fina Climent ◽  
Eva González-Barca ◽  
Santiago Mercadal ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Tissue Microarrays ◽  
Prognostic Impact ◽  
Germinal Center B Cell ◽  
Large B Cell

Abstract Diffuse large B-cell lymphomas (DLBCLs) can be divided into germinal-center B cell–like (GCB) and activated-B cell–like (ABC) subtypes by gene-expression profiling (GEP), with the latter showing a poorer outcome. Although this classification can be mimicked by different immunostaining algorithms, their reliability is the object of controversy. We constructed tissue microarrays with samples of 157 DLBCL patients homogeneously treated with immunochemotherapy to apply the following algorithms: Colomo (MUM1/IRF4, CD10, and BCL6 antigens), Hans (CD10, BCL6, and MUM1/IRF4), Muris (CD10 and MUM1/IRF4 plus BCL2), Choi (GCET1, MUM1/IRF4, CD10, FOXP1, and BCL6), and Tally (CD10, GCET1, MUM1/IRF4, FOXP1, and LMO2). GEP information was available in 62 cases. The proportion of misclassified cases by immunohistochemistry compared with GEP was higher when defining the GCB subset: 41%, 48%, 30%, 60%, and 40% for Colomo, Hans, Muris, Choi, and Tally, respectively. Whereas the GEP groups showed significantly different 5-year progression-free survival (76% vs 31% for GCB and activated DLBCL) and overall survival (80% vs 45%), none of the immunostaining algorithms was able to retain the prognostic impact of the groups (GCB vs non-GCB). In conclusion, stratification based on immunostaining algorithms should be used with caution in guiding therapy, even in clinical trials.

IgG gene expression and its possible significance in prostate cancers

The Prostate ◽  
2011 ◽  
Vol 72 (6) ◽  
pp. 690-701 ◽  
Author(s):  
Yuxuan Liu ◽  
Zhengshan Chen ◽  
Na Niu ◽  
Qing Chang ◽  
Ruishu Deng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancers
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