Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients

Abstract

Background:Malignant pleural mesothelioma (MPM) is a rare and essentially incurable malignancy most often linked with occupational exposure to asbestos fibres. In common with other malignancies, the development and progression of MPM is associated with extensive dysregulation of cell cycle checkpoint proteins that modulate cell proliferation, apoptosis, DNA repair and senescence.Methods:The expression of cyclin-dependent kinase inhibitor p16/INK4A was evaluated by immunohistochemistry using tumour biopsy specimens from 88 MPM cases and a semi-quantitative score for p16/INK4A expression was obtained. Post-diagnosis survival and the survival benefit of chemotherapeutic intervention was correlated with p16/INK4A expression.Results:A low, intermediate and high score for p16/INK4A expression was observed for 45 (51.1%), 28 (31.8%) and 15 (17.1%) of the MPM cases, respectively. Those cases with intermediate or high p16/INK4A tumour expression had a significantly better post-diagnosis survival than those cases whose tumours lost p16 expression (log-rank P<0.001). Those patients with sustained p16/INK4A expression who received chemotherapy also had a better survival than those treated patients whose tumours had lost p16/INK4A expression (log-rank P<0.001).Conclusions:Sustained p16/INK4A expression predicts better post-diagnosis survival in MPM and also better survival following chemotherapeutic intervention.

Tamoxifen Suppresses the Growth of Malignant Pleural Mesothelioma Cells

“…The REN, MPP-89, Msto-211H (Instituto Scientifico Tumouri, Genoa, Italy), H2052 MCF-7 and MET5A (American Type Culture Collection, Teddington, UK) cell lines were routinely maintained as described previously (9). For experimental purposes, cells were maintained in oestrogen-free medium for 24 h prior to treatment (10).…”

Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight

“…The 9p21 locus harboring CDKN2A is frequently inactivated in mesothelioma (6). Cdkn2a inactivation is a key driver of MPM in a conditional mouse model (7), and CDKN2A loss is associated with shorter survival in patients with MPM (8). CDKN2A encodes two important tumor suppressor proteins via alternative open reading frames, p16 Ink4a and p14 Arf that govern the activity of the retinoblastoma (pRb) and p53 pathways, respectively (9).…”

Heterogeneous Contributing Factors in MPM Disease Development and Progression: Biological Advances and Clinical Implications

“…Interestingly, over 75% of patients with mesothelioma have only P16 INK4a deletions, and these patients generally have poor prognoses and shorter survival rates; almost 30% of primary tumors have been reported to have methylated P16 INK4a [ 26 , 58 ]. Moreover, sustained P16 INK4a expression is associated with better survival in patients after chemotherapy, regardless of histological subtypes, and deletion of P16 INK4a correlates with poor outcomes [ 37 , 59 ].…”