A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma

Sánchez-Espiridión, Beatriz; Montalbán, Carlos; Lopez, Angel Alfonso Velarde; Menárguez, Javier; Sabı́n, Pilar; Ruíz-Marcellán, Carmen; López, Andrés; Ramos, Rafael; Rodríguez, José A.; Cánovas, Araceli; Camarero, Carmen; Canales, Miguel; Alvés, Javier; Arranz, Reyes; Acevedo, Agustín; Salar, Antonio; Serrano, Sergio; Bas, Águeda; Moraleda, José Marı́a; Sánchez-Godoy, Pedro; Burgos, Fernando; Rayón, Consolación; Fresno, Manuel; Laraña, J García; García‐Cosío, Mónica; Santonja, Carlos; López, J.; Llanos, Marta; Mollejo, Manuela; González-Carreró, Joaquín; Marín, Ana Isabel; Forteza, Jerónimo; García‐Sanz, Ramón; Tomás, José Francisco; Morente, Manuel; Piris, Miguel Á.; Garcı́a, Juan F.

doi:10.1182/blood-2010-02-270009

Cited by 47 publications

(54 citation statements)

References 41 publications

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“…This gene signature was related to outcome in a selected series of advanced stage cHL patients using a different approach: RT-PCR analyses and integration of gene expression levels into a logistical regression model. 18 In this study, high expression of the LYZ or STAT1 genes was found to correlate with prolonged FFS and better outcome 18 in the final model. To better understand the discrepancies between different series, we used IHC to investigate four different potential TAM markers in two independent series of patients.…”

Section: Introductionmentioning

confidence: 98%

“…For survival analyses, we used four different IHC cut-off points, based on previous reports: median of IHC expression, 4 th quartile, 5% and 25%. 8,10,12,14 We performed quantitative RT-PCR analyses for the LYZ and STAT1 genes, as previously described, 18 using a group of 209 cases randomly selected on the basis of the availability of sufficient tissue for mRNA extraction, and extracting RNA from the whole tissue sections.…”

Section: Design and Methodsmentioning

confidence: 99%

“…8,18 Spearman's test was used to test correlations between quantitative variables. P<0.05 was considered significant.…”

Section: Design and Methodsmentioning

confidence: 99%

“…In this study, we also compared protein expression levels measured by IHC and gene expression levels measured by RT-PCR for the two genes included in the previous model, 18 LYZ and STAT1. There were no significant correlations between the variables (Spearman's test, data not shown).…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

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Immunohistochemical markers for tumor associated macrophages and survival in advanced classical Hodgkin's lymphoma

Sánchez-Espiridión¹,

Martín‐Moreno²,

Montalbán³

et al. 2012

Haematologica

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A subset of patients with advanced classical Hodgkin's lymphoma is refractory to standard therapies. Therefore, it is relevant to identify new biologically-based prognostic markers. Recently, tumor associated macrophages have been proposed as a factor that predicts survival, although contradictory results have also been reported. Here we analyzed four macrophage markers (CD68, CD163, LYZ, and STAT1) using immunohistochemistry and automated quantification, in two independent series of advanced classical Hodgkin's lymphoma (n=266 and 103 patients, respectively). Our results did not confirm that specific macrophage immunohistochemical markers could be used as surrogates for gene expression profiling studies. Survival analyses did not show correlation between CD163, LYZ or STAT1 and either failure-free or disease-specific survival. There was an association between CD68 and disease-specific survival, but it was not consistent in both series. In conclusion, individual tumor associated macrophage markers cannot be used to predict outcome before technical standardization and prospective validation in independent series of patients with comparable stages and treatments.Key words: Hodgkin's lymphoma, outcome, tumor associated macrophages. Hodgkin's lymphoma. Haematologica 2012;97(7): 1080-1084. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Sánchez-Espiridión B, Martin-Moreno AM, Montalbán C, Medeiros LJ, Vega F, Younes A, Piris MA, and Garcia JF. Immunohistochemical markers for tumor associated macrophages and survival in advanced classical ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nstage disease who had a survival rate of 100%. These results suggest that semi-quantitative assessment of CD68 + TAMs can be used to identify patients at high risk of disease relapse or progression, as well as patients with early-stage disease with low risk for relapse who are currently over-treated.11 However, this approach has a major drawback as the number of low-risk patients in the Steidl et al. study was low because very few cases of cHL had less than 5% of TAM. Therefore, about 72% of cases in the original report fall into the high-risk group 10 and might be selected for alternative treatments.Similar results about the predictive value of TAM in cHL have recently been reported by other groups. 12,13 However, the consistency of IHC markers in different series has not been clearly confirmed.14,15 Differences in the composition of the case series, technical variability, and different cut offs for expression of TAM associated markers could, in part, explain these diverse results. Also, roles for Epstein-Barr virus (EBV) and age as confounding factors have been claimed, since both variables influence the host immune response and TAM composition. 12,16We recently used GEP to identify specific genes associated with treatment failure in cHL patients 8,17 including gene signatures associated with reactive cells in the microenvironment. This gene signature was related to outcome in a selected series of advanced s...

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Section: Introductionmentioning

confidence: 98%

Section: Design and Methodsmentioning

confidence: 99%

“…8,18 Spearman's test was used to test correlations between quantitative variables. P<0.05 was considered significant.…”

Section: Design and Methodsmentioning

confidence: 99%

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

See 2 more Smart Citations

Immunohistochemical markers for tumor associated macrophages and survival in advanced classical Hodgkin's lymphoma

Sánchez-Espiridión¹,

Martín‐Moreno²,

Montalbán³

et al. 2012

Haematologica

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“…Although several reports found a significantly negative prognostic effect of its over-expression in Hodgkin/Reed-Sternberg cells, [28][29][30][31][32][33] other studies found no impact. [34][35][36] Possible reasons for the inter-study discrepancy include disparate study populations, technical differences, for example, different antibody clones, use of tissue microarray vs whole sections, inter-observer variability, different criteria of BCL2 positivity, and disparate use of the index of outcome.…”

Section: Discussionmentioning

confidence: 90%

LGALS3 as a prognostic factor for classical Hodgkin's lymphoma

et al. 2014

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LGALS3, a member of the lectin family, has an important role in tumor progression through inhibition of apoptosis.LGALS3 shares several significant structural properties with BCL2. In this study, we examined the prognostic significance of LGALS3 and BCL2 in uniformly treated classical Hodgkin's lymphoma. Diagnostic tissues from 110 patients with uniformly treated classical Hodgkin's lymphoma were evaluated retrospectively by immunohistochemical analysis of LGALS3 and BCL2 expression. The median follow-up time was 6.2 years (range, 0.2-17.3 years). Twenty-seven patients (25%) expressed LGALS3 protein in Hodgkin/Reed-Sternberg cells, which was associated with poor overall survival and event-free survival (P ¼ 0.007 and Po0.001). Fifteen patients (14%) expressed BCL2 protein in Hodgkin/Reed-Sternberg cells, which was not associated with overall survival and event-free survival (P ¼ 0.928 and P ¼ 0.900).There was no correlation between LGALS3 and BCL2 expression (P ¼ 0.193). Multivariate analysis identified LGALS3 protein as an independent prognostic factor for event-free survival (P ¼ 0.007). Subgroup analysis according to the Ann Arbor stage of classical Hodgkin's lymphoma showed that LGALS3 protein expression had a prognostic value in limited-stage classical Hodgkin's lymphoma (Po0.001). The results of this study suggest that LGALS3 is an independent prognostic factor in classical Hodgkin's lymphoma, and may allow the identification of a subgroup of patients with limited-stage classical Hodgkin's lymphoma who require more intensive therapy. Modern Pathology (2014) 27, 1338-1344; doi:10.1038/modpathol.2014.38; published online 7 March 2014 Keywords: BCL2; Hodgkin's lymphoma; LGALS3; prognosis Classical Hodgkin's lymphoma is a highly curable lymphoid malignancy. 1 However, despite important treatment advances, a minority of patients do not respond to therapy or relapse after optimal initial therapeutic strategy, and may require adapted firstline treatment. 2 While the International Prognostic Score is useful in clinical practice, it does not fully reflect the biological behavior of classical Hodgkin's lymphoma. 3 Galectins, a family of mammalian b-galactosidebinding lectin molecules, are implicated in inflammation and tumor progression. 4 LGALS3 is expressed in lymphoma and myeloma cells, 5,6 and has both pro-apoptotic and antiapoptotic functions. 7 A recent study demonstrated that high expression of LGALS3 protein in diffuse large B-cell lymphoma cells was associated with resistance to apoptosis. 6 Moreover, LGALS3 has an important role in angiogenesis and metastases in several malignancies, including B-cell lymphomas. [7][8][9] B-cell lymphoma-2 (BCL2) protein inhibits apoptosis by preventing cytochrome release from mitochondria, thus blocking oxidative cell destruction. Over-expression of BCL2 has been found in some solid malignancies and malignant lymphomas including classical Hodgkin's lymphoma. [10][11][12][13] The BCL2 family of antiapoptotic proteins contribute to the survival of Hodgkin/Reed-Sternberg cell...

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Pathway‐focused gene expression profiles and immunohistochemistry detection identify contrasting association of caspase 3 (CASP3) expression with prognosis in pediatric classical Hodgkin lymphoma

Vera‐Lozada

Segges

Stefanoff

et al. 2018

Hematological Oncology

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The search for clinically relevant molecular markers in classical Hodgkin lymphoma (cHL) is hampered by the histopathological complexity of the disease, resulting from the admixture of a small number of neoplastic Hodgkin and Reed-Sternberg (H-RS) cells with an abundant and heterogeneous microenvironment. In this study, we evaluated gene expression profiles of 11 selected genes previously proposed as a molecular score for adult cHL, aiming to validate its application in the pediatric setting. Assays were performed by RT-qPCR from formalin-fixed paraffin-embedded (FFPE) lymph nodes in 80 patients with cHL. Selected genes were associated with cell cycle (CENPF, CDK1, CCNA2, CCNE2, and HMMR), apoptosis (BCL2, BCL2L1, and CASP3), and monocytes/macrophages (LYZ and STAT1). Despite using controlled preanalytical and analytical strategies, we were not able to validate the 11-gene score to be applied in pediatric cHL. Principal component analysis (PCA) disclosed 3 components that accounted for 65.7% of the total variability. The second PC included microenvironment and apoptosis genes, from which CASP3 expression was associated with a short time of progression-free survival, which impact was maintained in the unfavorable risk group, Epstein-Barr virus-negative cases, and multivariate analysis (P < .05). Because this is a counterintuitive association, CASP3 active expression was assessed at the protein level in H-RS cells by double immunohistochemistry. In contrast to the association of mRNA levels with a poor therapeutic response, a high number of cleaved CASP3+ cells were associated with longer progression-free survival (P = .03) and overall survival (P = .002). Our results demonstrate the feasibility of using FFPE samples as RNA source for molecular prognostication, but argue against the concept of direct and wide applicability of molecular scores in cHL. We reinforce the potential of CASP3 as an interesting target to be explored in adult and pediatric cHL, and alert for its dual biological role in H-RS cells and tumor microenvironment.

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A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma

Cited by 47 publications

References 41 publications

Immunohistochemical markers for tumor associated macrophages and survival in advanced classical Hodgkin's lymphoma

Immunohistochemical markers for tumor associated macrophages and survival in advanced classical Hodgkin's lymphoma

LGALS3 as a prognostic factor for classical Hodgkin's lymphoma

Pathway‐focused gene expression profiles and immunohistochemistry detection identify contrasting association of caspase 3 (CASP3) expression with prognosis in pediatric classical Hodgkin lymphoma

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