A new polymorphism biomarker rs629367 associated with increased risk and poor survival of gastric cancer in chinese by up-regulated miRNA-let-7a expression.
BACKGROUND
Variant in pri-miRNA could affect miRNA expression and mature process or splicing efficiency, thus altering the hereditary susceptibility and prognosis of cancer. We aimed to assess miRNA-let-7 single nucleotide polymorphisms (SNP) associated with the risk and prognosis of gastric cancer (GC) as predicting biomarkers, and furthermore, its possible mechanisms.


METHODS
A two-stage case-control study was designed to screen four miRNA SNPs (pri-let-7a-2 rs629367 and rs1143770, pri-let-7a-1 rs10739971, pri-let-7f-2 rs17276588) in 107 GC patients, 107 atrophic gastritis (AG), and matched 124 controls using PCR-RFLP. Two promising SNPs were validated in another independent 1949 samples (including 579 gastric cancer patients, 649 atrophic gastritis and 721 controls) using Sequenom MassARRAY platform and sequencing.


RESULTS
We found that pri-let-7a-2 rs629367 CC variant genotype was associated with increased risks of gastric cancer and atrophic gastritis by 1.83-fold and 1.86-fold, respectively. For gastric cancer prognosis, patients with rs629367 CC genotype had significantly poorer survival than patients with AA genotype (log-rank P = 0.004). We further investigated the let-7a expression levels in serum and found that let-7a expression elevated gradually for rs629367 AA, CA, CC genotype in the atrophic gastritis group (P = 0.043). Furthermore, we confirmed these findings in vitro study by overexpressing let-7a carrying pri-let-7a-2 wild-type A or polymorphic-type C allele (P<0.001).


CONCLUSIONS
pri-let-7a-2 rs629367 CC genotype could increase the risks of gastric cancer as well as atrophic gastritis and was also associated with poor survival of gastric cancer, which possibly by affecting the mature let-7a expression, and could serve as a predicting biomarker for high-risk and poor prognosis of gastric cancer.
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, Liaoning, China.
Qian
Q
Xu
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, Liaoning, China.
Qiguan
Q
Dong
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, Liaoning, China.
Caiyun
C
He
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, Liaoning, China.
Wenjing
W
Liu
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, Liaoning, China.
Liping
L
Sun
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, Liaoning, China.
Jingwei
J
Liu
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, Liaoning, China.
Chengzhong
C
Xing
Gastrointestinal Surgery and Department 4 of General Surgery, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
Xiaohang
X
Li
Hepatobiliary Surgery and Department 1 of General Surgery, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
Bengang
B
Wang
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Affiliated Hospital of China Medical University, and Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang, Liaoning, China.
Yuan
Y
Yuan
D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005757:Gastritis, Atrophic / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*
D035683:MicroRNAs