Serum Calretinin and Genetic Variability as a Prognostic and Predictive Factor in Malignant Mesothelioma

Our plain-English summary of Serum Calretinin and Genetic Variability as a Prognostic and Predictive Factor in Malignant Mesothelioma, by C. Zupanc, A. Franko, D. Štrbac, et al (International Journal of Molecular Sciences, 2023).

The study

• Authors: C. Zupanc, A. Franko, D. Štrbac, V. Kovač, V. Dolžan, K. Goričar
• Journal: International Journal of Molecular Sciences
• Published: 2023;25(1)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Calretinin is a promising diagnostic biomarker for malignant mesothelioma (MM), but less is known about its prognostic role. Our aim was to evaluate the association between serum calretinin concentration or genetic factors and the survival or outcome of cisplatin-based chemotherapy in MM. Our study included 265 MM patients. Serum calretinin concentration was determined using ELISA. Patients were genotyped for seven polymorphisms in CALB2, E2F2, MIR335, NRF1, and SEPTIN7 using competitive allele-specific PCR. Nonparametric tests, logistic regression, and survival analysis were used for statistical analysis. Higher serum calretinin concentration was associated with shorter progression-free (PFS) (HR = 1.18 (1.02-1.37), p = 0.023) and overall survival (OS) (HR = 1.20 (1.03-1.41), p = 0.023), but the association was not significant after adjusting for clinical factors (HR = 1.05 (0.85-1.31), p = 0.653 and HR = 1.06 (0.84-1.34), p = 0.613, respectively). SEPTIN7 rs3801339 and MIR335 rs3807348 were associated with survival even after adjustment (HR = 1.76 (1.17-2.64), p = 0.007 and HR = 0.65 (0.45-0.95), p = 0.028, respectively). Calretinin concentration was higher in patients who progressed after treatment with cisplatin-based chemotherapy (1.68 vs. 0.45 ng/mL, p = 0.001). Calretinin concentration above 0.89 ng/mL was associated with shorter PFS and OS from the start of chemotherapy (HR = 1.88 (1.28-2.77), p = 0.001 and HR = 1.91 (1.22-2.97), p = 0.004, respectively), even after adjusting for clinical factors (p < 0.05). MIR335 rs3807348 was associated with a better response to chemotherapy (OR = 2.69 (1.17-6.18), p = 0.020). We showed that serum calretinin is associated with survival and chemotherapy treatment outcomes in MM and could serve as a predictive biomarker.

In plain English

This retrospective study included 265 patients with pleural or peritoneal malignant mesothelioma treated at the Institute of Oncology Ljubljana, Slovenia, from November 2001 to March 2019. Of these, 239 received cisplatin-based chemotherapy. The authors measured serum calretinin, a protein, at diagnosis (available for 146 patients) and tested seven gene variants linked to calretinin. Across all patients, higher calretinin was associated with shorter progression-free and overall survival, but not significantly after adjusting for clinical factors. Among chemotherapy patients, calretinin was higher in those whose treatment outcome was disease progression than in those who responded or remained stable (median 1.68 versus 0.45 ng/mL). Patients above 0.89 ng/mL, a cutoff derived from these data, had shorter progression-free survival (hazard ratio 1.88, 95% CI 1.28–2.77) and shorter overall survival (hazard ratio 1.91, 95% CI 1.22–2.97) from the start of chemotherapy; both remained significant after adjustment. Variants in the SEPTIN7 and MIR335 genes were associated with survival, and the MIR335 variant with better chemotherapy response. The authors concluded that serum calretinin could serve as a predictive biomarker for patients given cisplatin-based chemotherapy, and called for validation in an independent population.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective study of patients' clinical records, blood serum calretinin and genotypes, plus an analysis of public tumor gene-expression data (TCGA, via the GEPIA2 tool)
• Who was studied: 265 patients with histologically confirmed pleural or peritoneal malignant mesothelioma treated at the Institute of Oncology Ljubljana (Slovenia), November 2001 to March 2019. 239 were treated with cisplatin-based chemotherapy. 197 (74.3%) were male, 235 (88.7%) had pleural MM and 204 (77.0%) had the epithelioid type. Serum calretinin at diagnosis was available for 146 patients.
• Exposure: The factors studied were serum calretinin concentration at diagnosis (measured by ELISA) and seven gene variants (in CALB2, E2F2, MIR335, NRF1 and SEPTIN7). Asbestos exposure was recorded as a clinical characteristic: 198 patients (75.0%) were listed as exposed. No fiber types were named.
• Main results:
  • All patients, survival from diagnosis: higher serum calretinin was associated with shorter progression-free survival (HR = 1.18, 95% CI 1.02–1.37, p = 0.023) and shorter overall survival (HR = 1.20, 95% CI 1.03–1.41, p = 0.023).
  • After adjusting for significant clinical factors, these associations were no longer statistically significant: progression-free survival HR = 1.05 (95% CI 0.85–1.31, p = 0.653); overall survival HR = 1.06 (95% CI 0.84–1.34, p = 0.613).
  • Patients treated with cisplatin-based chemotherapy, by treatment outcome: median serum calretinin was 1.68 (0.58–4.20) ng/mL in patients whose chemotherapy outcome was disease progression, versus 0.45 (0.21–1.07) ng/mL in patients with complete response, partial response or stable disease (p = 0.001). This is the treatment-response assessment, not eventual progression (214 of the 239 treated patients eventually progressed).
  • Chemotherapy patients with calretinin above 0.89 ng/mL, a cutoff determined by ROC curve analysis in this same data, had higher odds of disease progression (OR = 7.50, 95% CI 2.50–22.47, p < 0.001). The association remained significant after adjusting for clinical factors (p = 0.016).
  • Chemotherapy patients with calretinin above 0.89 ng/mL had shorter progression-free survival (HR = 1.88, 95% CI 1.28–2.77, p = 0.001) and shorter overall survival (HR = 1.91, 95% CI 1.22–2.97, p = 0.004) from the start of chemotherapy. These are unadjusted estimates. Both remained significant after adjustment (p = 0.006 and 0.049).
  • Calretinin above the median or above 0.89 ng/mL was not significantly associated with response rate (complete or partial response) among chemotherapy patients.
  • All patients: carriers of two polymorphic SEPTIN7 rs3801339 alleles had shorter progression-free survival from diagnosis (HR = 1.47, 95% CI 1.02–2.13, p = 0.039; adjusted HR = 1.76, 95% CI 1.17–2.64, p = 0.007).
  • All patients: MIR335 rs3807348 heterozygotes had longer overall survival from diagnosis than carriers of two reference alleles (HR = 0.69, 95% CI 0.49–0.98, p = 0.038; adjusted HR = 0.65, 95% CI 0.45–0.95, p = 0.028).
  • Chemotherapy patients: carriers of at least one MIR335 rs3807348 polymorphic allele had better treatment response (OR = 2.41, 95% CI 1.19–4.87, p = 0.015; adjusted OR = 2.69, 95% CI 1.17–6.18, p = 0.020).
  • None of the studied gene variants was significantly associated with progression-free or overall survival from the start of chemotherapy.
  • In public TCGA mesothelioma tumor data (not this study's patients), high CALB2 (calretinin gene) expression in tumor tissue was associated with longer overall survival (HR = 0.43, p < 0.001).
• The authors' conclusion: The authors concluded that serum calretinin was associated with shorter survival but was not an independent prognostic factor in their study. They concluded it could serve as a predictive biomarker in mesothelioma patients treated with cisplatin-based chemotherapy.
• Limitations the authors state:
  • Serum calretinin was available only for a subgroup of patients, and no tumor tissue samples were available to compare calretinin expression.
  • The tissue gene-expression analysis could not include miR-335, because its data are not in the GEPIA2 database.
  • Other genetic factors not studied could also influence calretinin expression.
  • The results need further large studies and validation in an independent population.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Calretinin, Mesothelioma, Biomarker, Cisplatin, Chemotherapy, Overall Survival.

Related studies

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• Low calretinin expression and high neutrophil-to-lymphocyte ratio are poor prognostic factors in patients with malignant mesothelioma undergoing extrapleural pneumonectomy — S.C. Kao, S. Klebe, et al. (2011)
• Serum Calretinin as a Biomarker in Malignant Mesothelioma — C. Zupanc, A. Franko, et al. (2021)
• Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin — J. Wörthmüller, V. Salicio, et al. (2019)
• Mesothelin, Calretinin, and Megakaryocyte Potentiating Factor as Biomarkers of Malignant Pleural Mesothelioma — C. Jiménez-Ramírez, S. Casjens, et al. (2019)
• Development of an enzyme-linked immunosorbent assay for the detection of human calretinin in plasma and serum of mesothelioma patients — I. Raiko, I. Sander, et al. (2010)

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