Characterization of functional excision repair cross-complementation group 1 variants and their association with lung cancer risk and prognosis.
OBJECTIVE
The excision repair cross-complementation group 1 (ERCC1) plays a pivotal role in DNA repair and has been linked to protection against carcinogenesis and resistance to platinum-based anticancer drugs. We tested whether genetic variants in the ERCC1 gene are associated with susceptibility to lung cancer and efficacy of platinum-chemotherapy in patients with small cell lung cancer (SCLC).


METHODS
Thirty individual DNA samples were sequenced to search for single-nucleotide polymorphisms, and the functions of the variants were investigated by a series of biochemical assays. A case-control study was done in 988 patients with lung cancer and 986 control subjects. According to the genotypes, a comparison of chemotherapy outcome in 162 SCLC patients was executed. Overall survival was computed by Cox model adjusted for clinical factors.


RESULTS
We identified two functional variants in the ERCC1 5'-flanking region, -433T>C and 262G>T, which cooperatively influence transcriptional regulation of ERCC1. The 262G allele had significantly lower affinity to bind nuclear protein(s) and was associated with decreased ERCC1 RNA expression. The case-control analysis showed that the -433C and 262G alleles are associated with an increased susceptibility to lung cancer, alone and in a gene-smoking joint effect manner. In contrast, the analysis of chemotherapy outcome of SCLC patients revealed that the 262G allele is associated with better drug response and longer survival time compared with the 262T allele.


CONCLUSIONS
These findings are consistent with the notion that DNA repair is a double-edged sword in cancer and suggest that functional single-nucleotide polymorphisms in ERCC1 might serve as simple and less invasive biomarkers for personalized chemotherapy of platinum-based anticancer drugs.
Yu
Dianke
D
Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China.
Zhang
Xuemei
X
Liu
Ju
J
Yuan
Peng
P
Tan
Wen
W
Guo
Yongli
Y
Sun
Tong
T
Zhao
Dan
D
Yang
Ming
M
Liu
Junniao
J
Xu
Binghe
B
Lin
Dongxin
D
D000483:Alleles; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases