Influence of hMLH1 methylation, mismatch repair deficiency and microsatellite instability on chemoresistance of testicular germ-cell tumors.
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.


METHODS
We investigated 15 refractory and 36 chemosensitive GCTs for immunohistochemical loss of hMLH1, hMSH2 and hMSH6 protein 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%). hMLH1 methylation was found in 11 cases (21.60%) and was highly correlated with loss of hMLH1 expression (p < 0.0001) and with immunohistochemically-detected MMR deficiency (p = 0.0005). MSI was found in 16 cases (31.4%). There was no correlation between hMLH1 methylation and MSI. Neither hMLH1 methylation status, nor MSI correlated with any of the clinicopathological parameters investigated (tumor stage, histology, resistance to systemic treatment).


CONCLUSIONS
hMLH1 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.
Olasz
Judit
J
Department of Pathogenetics, National Institute of Oncology, Budapest, Hungary.
Mándoky
László
L
Géczi
Lajos
L
Bodrogi
István
I
Csuka
Orsolya
O
Bak
Mihály
M
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology; D020137:Base Pair Mismatch; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D019175:DNA Methylation; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D009367:Neoplasm Staging; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000235:genetics*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D002945:Cisplatin