Association Of MtDNA D-Loop And Romol Gene Genetic Polymorphisms With Risk Of Gastric Cancer In North-western Population Of China

Background:Various frequencies of mutations were described in the mitochondrial DNA (mtDNA) displacement loop(D-loop) region in gastric cancer (GC). The mitochondrial inner-membrane protein reactive oxygen species modulator 1 (Romo1), which induces ROS generation, was found increased expression in most tumor cell lines. Romol-derived ROS can cause oxidative damage and apoptosis of normal and cancer cells. The generation mechanism and the role of these mtDNA related genes polymorphisms in GC development remain unclear.Aim:The aim of our study was to evaluate the association of common polymorphisms detected in mtDNA D-loop region (mononucleotide repetitive D310, single nucleotide polymorphism (SNP) D16521) and Romol gene (SNP rs6060566, rs6060567 and rs17092980) with susceptibility to gastric cancer (GC) in northwestern Chinese population, to provide evidence for the early diagnosis, therapy and prevention of GC.Methods:180 GC patients and 218 healthy controls were investigated using PCR-DHPLC (denaturing high pressure liquid chromatography) assay. Genotype and allele distributions and haplotype construction were analyzed in case-control study. The comparisons were also conducted according to different groups of gender, age and histological grade of GC.Results:Heteroplasmy 7C/8C and 8C/9C for D310 were significantly different between GC cases and controls (p=0.011, p=0.022, respectively). Heteroplasmy C/T for D16521 was significantly correlated with GC (p=0.023), and homoplasmy C/C showed association with histological grade of GC (p=0.009 in moderately-differentiated and poorly-differentiated adenocarcinoma, respectively). Haplotype analysis of D310 & D16521 showed 7C/T,8C/C and 9C/C had significant association with GC risk(p=0.016336, p=0.008268, p=0.000269). rs6060566 and rs6060567 polymorphisms in Romol had higher risk of GC (p<0.05). We did not find any mutation for rs17092980 in Romol which is monopolymrophism in all the samples studied. Haplotype analysis of rs6060566 and rs6060567 showed T/G and C/T had significant correlation with GC risk(p=0.011216, p=1.66e-005).Conclusion:These findings suggested genetic polymorphisms of mtDNA D-Loop and Romol gene were associated with significant alternative risk of GC in north-western population of China. Moreover, D16521 homoplasmy closely related to histological grades in GC patients, it is a valuable potential marker in clinical progression.