Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy

Our plain-English summary of Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy, by R.F. Walter, C. Vollbrecht, R. Werner, et al (Journal of Cancer, 2016).

The study

• Authors: R.F. Walter, C. Vollbrecht, R. Werner, T. Mairinger, J. Schmeller, E. Flom, J. Wohlschlaeger, N. Barbetakis, D. Paliouras, F. Chatzinikolaou, V. Adamidis, K. Tsakiridis, P. Zarogoulidis, G. Trakada, D.C. Christoph, K.W. Schmid, F.D. Mairinger
• Journal: Journal of Cancer
• Published: 2016;7(13):1915-1925
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare, predominantly asbestos-related and biologically highly aggressive tumour leading to a dismal prognosis. Multimodality therapy consisting of platinum-based chemotherapy is the treatment of choice. The reasons for the rather poor efficacy of platinum compounds remain largely unknown.

Material And Methods: For this exploratory mRNA study, 24 FFPE tumour specimens were screened by digital gene expression analysis. Based on data from preliminary experiments and recent literature, a total of 366 mRNAs were investigated using a Custom CodeSet from NanoString. All statistical analyses were calculated with the R i386 statistical programming environment.

Results: CDC25A and PARP1 gene expression were correlated with lymph node spread, BRCA1 and TP73 expression levels with higher IMIG stage. NTHL1 and XRCC3 expression was associated with TNM stage. CHECK1 as well as XRCC2 expression levels were correlated with tumour progression in the overall cohort of patients. CDKN2A and MLH1 gene expression influenced overall survival in this collective. In the adjuvant treated cohort only, CDKN2A, CHEK1 as well as ERCC1 were significantly associated with overall survival. Furthermore, TP73 expression was associated with progression in this subgroup.

Conclusion: DNA-damage response plays a crucial role in response to platin-based chemotherapeutic regimes. In particular, CHEK1, XRCC2 and TP73 are strongly associated with tumour progression. ERCC1, MLH1, CDKN2A and most promising CHEK1 are prognostic markers for OS in MPM. TP73, CDKN2A, CHEK1 and ERCC1 seem to be also predictive markers in adjuvant treated MPMs. After a prospective validation, these markers may improve clinical and pathological practice, finally leading to a patients' benefit by an enhanced clinical management.

In plain English

This was an exploratory, retrospective laboratory study of stored tumour tissue from 24 patients with malignant pleural mesothelioma. The patients were treated at two centres in Essen, Germany, between 2005 and 2009. All received platinum-based chemotherapy, mostly cisplatin with pemetrexed. Twelve samples were taken in the adjuvant setting and twelve in the neoadjuvant setting. The authors measured the mRNA expression levels of 366 genes, including reference genes, and focused their results on 30 involved in DNA-damage recognition and repair. In the whole group, some gene levels were statistically linked to stage and lymph node spread. CHEK1 (p=0.0362) and XRCC2 (p=0.0053) were linked to tumour progression, and CDKN2A (p=0.0387) and MLH1 (p=0.0344) to overall survival. No gene was linked to progression-free survival. In the adjuvant group only, TP73 was linked to progression (p=0.0303), and CDKN2A, CHEK1 and ERCC1 were linked to overall survival. The authors concluded that DNA-damage response plays a crucial role in response to platinum-based chemotherapy and that these markers should be validated prospectively. The article did not report on patients' asbestos exposure.

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: Exploratory retrospective study measuring gene expression (mRNA) in stored formalin-fixed paraffin-embedded tumour samples, using NanoString digital gene expression analysis
• Who was studied: 24 patients with malignant pleural mesothelioma (22 men and 2 women per Table 1) treated at the West German Cancer Centre or West German Lung Centre, Essen, Germany, 2005 to 2009. Twelve were adjuvant-treated and twelve neoadjuvant-treated. Follow-up ended August 31, 2014; 23 of 24 had died and 19 of 24 had progressed.
• Exposure: Not asbestos. The study concerned platinum-based chemotherapy: cisplatin plus pemetrexed in most patients, carboplatin plus pemetrexed in two, and cisplatin plus carboplatin plus pemetrexed in one (Table 1). Expression of 366 mRNAs, including reference genes, was measured.
• Main results:
  • 366 mRNAs, including reference genes, were measured, and the analysis was narrowed to 30 targets involved in DNA-damage recognition and repair.
  • High BRCA1 and TP73 levels were correlated with higher IMIG stage (p=0.0067 and p=0.0284 in the text; Table 3 gives 0.0078 for BRCA1).
  • Low CDC25A expression was correlated with lymph node invasion (p=0.0358), and high PARP1 expression was associated with lymph node spread (p=0.0078).
  • Lower NTHL1 (p=0.0478) and higher XRCC3 (p=0.0026) expression were associated with higher T-stage.
  • Overall cohort: CHEK1 (p=0.0362) and XRCC2 (p=0.0053) expression were associated with objective tumour progression.
  • Overall cohort: no associations with progression-free survival were found. CDKN2A (p=0.0387) and MLH1 (p=0.0344) expression influenced overall survival. The direction of these survival associations is not stated in the text.
  • Adjuvant-treated patients: increased TP73 expression was associated with tumour progression during therapy (p=0.0303).
  • Adjuvant-treated patients: CDKN2A (p=0.0297), CHEK1 (p=0.0162) and ERCC1 (p=0.0455) expression were correlated with overall survival.
  • H2AFX (p=0.0100), PCNA (p=0.0242) and XRCC1 (p=0.0387) expression increased during platinum-based chemotherapy.
  • No investigated marker was correlated with distant metastasis, and no association with gender was found.
• The authors' conclusion: The authors concluded that DNA-damage response plays a crucial role in response to platinum-based chemotherapy. They considered CHEK1, XRCC2 and TP73 strongly associated with tumour progression, and MLH1, CHEK1, ERCC1 and CDKN2A prognostic markers for overall survival. They described TP73, CDKN2A, CHEK1 and ERCC1 as seeming to be predictive markers in adjuvant-treated patients, to be validated prospectively.
• Limitations the authors state:
  • The authors called the study exploratory and recommended validation in a larger prospective study.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, Prognosis, Multimodal Therapy, IMIG, CDKN2A, Overall Survival.

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