Epithelioid Mesothelioma Patients with Very Long Survival Display Defects in DNA Repair

Our plain-English summary of Epithelioid Mesothelioma Patients with Very Long Survival Display Defects in DNA Repair, by M. Ganzinelli, F. Guffanti, A. Ianza, et al (Cancers, 2023).

The study

• Authors: M. Ganzinelli, F. Guffanti, A. Ianza, N. Sobhani, S. Crovella, F. Zanconati, C. Bottin, M. Confalonieri, S. Fumagalli, A. Guglielmi, D. Generali, G. Damia
• Journal: Cancers
• Published: 2023;15(17)
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Aim: DNA repair has an important role in malignant pleural mesothelioma (MPM) tumorigenesis and progression. Prognostic/predictive biomarkers for better management of MPM patients are needed. In the present manuscript, we analyzed the expression of more than 700 genes in a cohort of MPM patients to possibly find biomarkers correlated with survival.

Methods: A total of 54 MPM patients, all with epithelioid histology, whose survival follow-up and formalin-fixed paraffin-embedded tumors were available, were included in the study. Gene expression profiles were evaluated using a Nanostring platform analyzing 760 genes involved in different cellular pathways. The percentages of proliferating tumor cells positive for RAD51 and BRCA1 foci were evaluated using an immunofluorescence assay, as a readout of homologous recombination repair status.

Results: Patient median survival time was 16.9 months, and based on this value, they were classified as long and short survivors (LS/SS) with, respectively, an overall survival ≥ and <16.9 months as well as very long and very short survivors (VLS/VSS) with an overall survival ≥ than 33.8 and < than 8.45 months. A down-regulation in the DNA damage/repair expression score was observed in LS and VLS as compared to SS and VSS. These findings were validated by the lower number of both RAD51 and BRCA1-positive tumor cells in VLS as compared to VSS.

Conclusions: The down-regulation of DNA repair signature in VLS was functionally validated by a lower % of RAD51 and BRCA1-positive tumor cells. If these data can be corroborated in a prospective trial, an easy, cost-effective test could be routinely used to better manage treatment in MPM patients.

In plain English

This retrospective study examined stored tumors from 54 patients with epithelioid malignant pleural mesothelioma treated in Trieste, Italy, between 2006 and 2018. Information on asbestos exposure, jobs and smoking was not available for most patients. The authors measured expression of 760 genes. They also counted proliferating tumor cells with RAD51 and BRCA1 'foci', which they used as a readout of homologous recombination DNA repair status. Median survival was 16.9 months. Patients were grouped as long or short survivors around this value, and as very long (33.8 months or more) or very short (under 8.45 months) survivors, 12 each. A DNA damage repair gene expression score was lower in long than in short survivors, and in very long than in very short survivors. Very long survivors had a statistically significantly lower percentage of proliferating tumor cells with five or more RAD51 foci than very short survivors, and the same was true for BRCA1 foci. The authors said these data point to a possible inactivation of homologous recombination repair in longer survivors. They said the results need confirming in prospective studies, and they could not find out which chemotherapy patients received.

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 laboratory study of archived tumor samples (gene expression profiling and immunofluorescence), with results compared against patients' overall survival
• Who was studied: 54 patients with epithelioid malignant pleural mesothelioma (45 male, 9 female; median age at diagnosis 73 years, range 56 to 86), treated at the Azienda Sanitaria Universitaria Giuliano Isontina of Trieste, Italy, between 2006 and 2018. Tumor samples were taken at diagnosis, before any systemic treatment. There were 28 long and 26 short survivors, and 12 very long and 12 very short survivors.
• Exposure: Asbestos exposure was not studied: occupational, para-occupational, asbestos exposure and smoking information was not available for most patients. The study examined tumor gene expression (760 genes, including a 44-gene DNA damage repair pathway) and the percentage of proliferating (geminin-positive) tumor cells with 5 or more RAD51, BRCA1 or gamma-H2AX foci per nucleus.
• Main results:
  • Median survival of the 54 patients was 16.9 months (Table 1 gives the range as 1.3 to 107.7 months).
  • Long survivors were younger than short survivors (68.4 years plus or minus 1.8 vs. 73.9 years plus or minus 1.2, p less than 0.0141). Ages did not differ between the very short and very long survivor groups (p = 0.22).
  • Of 13 gene pathways, all showed a trend toward higher expression scores in long than in short survivors except the DNA damage repair (DDR) pathway, which was downregulated in long survivors. The authors report this was confirmed in very long versus very short survivors.
  • Long survivors had higher NR4A1, NR4A3, GRIN2A and FOS mRNA levels than short survivors. These genes were linked to survival only in univariate analysis, not in multivariate analysis.
  • Foci were scored as the percentage of proliferating (geminin-positive) tumor cells with 5 or more foci per nucleus. Very long survivors had a statistically significantly lower percentage of such cells than very short survivors, both for RAD51 and for BRCA1 (p less than 0.001, t-test, per the figure legend).
  • The percentage of proliferating tumor cells with gamma-H2AX foci was similar in very long and very short survivors.
  • RAD51 mRNA expression was not associated with the percentage of RAD51-positive proliferating cells (Spearman correlation index = 0.1765, p = 0.4836).
  • BRCA1 mRNA expression showed a slight association with the percentage of BRCA1-positive proliferating cells (Spearman correlation index = 0.5880, p = 0.0233).
  • The authors said these data point to a possible inactivation of homologous recombination repair in epithelioid mesothelioma patients with longer survival.
• The authors' conclusion: The authors concluded that longer-surviving patients with epithelioid pleural mesothelioma showed down-regulation of the DNA damage repair gene expression signature and lower RAD51 and BRCA1 foci scores than shorter survivors. They suggested these patients may be enriched for inactivated homologous recombination repair. They said that, if validated, the test could help tailor chemotherapy.
• Limitations the authors state:
  • The authors could not find out, for all patients, whether they received chemotherapy and of what type. They therefore could not explore the markers' role in predicting response to treatment.
  • The four genes linked to survival (NR4A1, NR4A3, GRIN2A, FOS) were associated with survival only in univariate analysis. The authors say this strongly limits their clinical value.
  • The findings need to be validated in prospective studies.

Topics

Medical terms in this study, explained in our Lexicon: Epithelioid, Mesothelioma, Pleural Mesothelioma, Carcinogenesis, Biomarker, Histology, Median Overall Survival, Overall Survival.

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• A defect of amphiregulin release predicted longer survival independently of YAP expression in patients with pleural mesothelioma in the IFCT-0701 MAPS phase 3 trial — E. Maille, J. Levallet, et al. (2022)
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• Long-term outcomes after chest wall resection and repair with titanium bars and sternal plates — H. Clermidy, G. Fadel, et al. (2022)
• EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors — H. Kothmaier, F. Quehenberger, et al. (2008)

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