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