Influence of hMLH1 methylation, mismatch repair deficiency and microsatellite instability on chemoresistance of testicular germ-cell tumors
Olasz, J.; Mándoky, László.; Géczi, L.; Bodrogi, Ián.; Csuka, O.; Bak, Mály.
Anticancer Research 25(6b): 4319-4324
2005
ISSN/ISBN: 0250-7005 PMID: 16309235 Document Number: 588033
Background: Cisplatin-based chemotherapy can cure more than 80% of metastatic germ-cell testicular tumors (GCTs). The response to cisplatin-based chemotherapy has been related to Microsatellite Instability (MSI), which is caused by genetic or epigenetic changes in genes of the DNA Mismatch Repair (MMR) pathway. Patients and Methods: We investigated 15 refractory and 36 chemosensitive GCTs for immunohistochemical loss of hMLH1, hMSH2 and hMSH6protein expressions, in conjunction with hMLH1 gene methylation and MSI of GCTs, with a complete follow-up. Results: A loss of either of the MMR protein expressions was detected in 14 cases (27.5%). Pathological hMLH1 protein expression was seen in 10 cases (19.6%). hMLHI methylation was found in 11 cases (21.6%) and was highly correlated with loss of hMLHI expression (p<0.0001) and with immunohistochemical -detected MMR deficiency (p = 0.0005). MSI was found in 16 cases (31.4%). There was no correlation between hMLHI methylation and MSI. Neither hMLHI methylation status, nor MSI correlated with any of the clinicopathological parameters investigated (tumor stage, histology, resistance to systemic treatment). Conclusion: hMLHI gene methylation was detected as a common alteration in GCTs, and correlated with the loss of hMLH1 protein expression (p < 0.0001). Neither hMLH1 gene methylation, MMR deficiency, nor MSI showed a relationship with the relevant clinicopathological parameters.