DNA polymerase η protein expression predicts treatment response and survival of metastatic gastric adenocarcinoma patients treated with oxaliplatin-based chemotherapy.
BACKGROUND
DNA polymerase η (pol η) is capable of bypassing DNA adducts produced by cisplatin or oxaliplatin and is associated with cellular tolerance to platinum. Previous studies showed that defective pol η resulted in enhanced cisplatin or oxaliplatin sensitivity in some cell lines. The purpose of the present study was to investigate the role of pol η protein expression in metastatic gastric adenocarcinoma.


METHODS
Four gastric adenocarcinoma cell lines were chosen to explore the relationship between pol η protein expression and oxaliplatin sensitivity by western blotting and MTT assay. Eighty metastatic gastric adenocarcinoma patients treated with FOLFOX or XELOX regimen as first-line chemotherapy were analyzed, corresponding pretreatment formalin-fixed paraffin-embedded tumor tissues were used to detect pol η protein expression by immunohistochemistry. Relationship between pol η protein expression and clinical features and outcome of these patients was analyzed.


RESULTS
A positive linear relationship between pol η protein expression and 48 h IC50 values of oxaliplatin in four gastric cancer cell lines was observed. Positivity of pol η protein expression was strongly associated with poor treatment response, as well as shorter survival at both univariate (8 versus 14 months; P < 0.001) and multivariate (hazard ratio, 4.555; 95% confidence interval, 2.461-8.429; P < 0.001) analysis in eighty metastatic gastric adenocarcinoma patients.


CONCLUSIONS
Our study indicates that pol η is a predictive factor of treatment response and survival of metastatic gastric adenocarcinoma patients treated with FOLFOX or XELOX as first-line chemotherapy. Therefore confirming the value of pol η in studies with prospective design is mandatory.
State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
Kai-yuan
KY
Teng
Miao-zhen
MZ
Qiu
Zhuang-hua
ZH
Li
Hui-yan
HY
Luo
Zhao-lei
ZL
Zeng
Rong-zhen
RZ
Luo
Hui-zhong
HZ
Zhang
Zhi-qiang
ZQ
Wang
Yu-hong
YH
Li
Rui-hua
RH
Xu
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D012372:ROC Curve; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult; D000099270:Y-Family DNA Polymerases
D000970:Antineoplastic Agents; D004259:DNA-Directed DNA Polymerase; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases