Mitochondrial DNA Copy Number Is Associated With Risk Of Head And Neck Squamous Cell Carcinoma In Chinese Population

Head and neck carcinoma(HNC)is the sixth most common cancer worldwide,accounting for the 6%of all malignant cancer.There are more than 60 thousand new cases of HNC each year in the world,of which 2/3 in the developing world.Head and neck cancer mainly originated from the mucous membrane in the upper respiratory and digestive tract,including the mouth,pharynx(nasopharynx,oropharynx,hypopharynx)and the throat,90%of which is with the pathological type of squamous cell carcinoma(Head and neck squamous cell carcinoma,HNSCC).In addition to nasopharyngeal carcinoma(the infection of EB),smoking,drinking and HPV infection is often considered as the main risk factors for head and neck squamous cell carcinoma.The aerobic respiration and oxidative phosphorylation happened in the mitochondria is the main energy source of eukaryotic cells.Through participated in energy and material metabolism,mitochondria affect eukaryotic cell and organism growth,development and function realization and so on.The genetic influence of mitochondria which called mitochondrial genome,include mitochondrial DNA and nuclear DNA,two of which work together to ensure the proper functioning of mitochondria.Relative to nuclear DNA,the mitochondrial DNA happen mutation more easily and the mutation rate is 10-200 times higher,because of its special structure and high active oxygen environment.The point mutations and copy number variation of mitochondrial DNA may be the reason for mitochondrial dysfunction.The process of oxidative phosphorylation can be inhibited by cell mitochondrial dysfunction,cause the body to produce a large number of ROS,leading to oxidative stress response and the mutations and injury of nuclear DNA and mitochondrial DNA mutations and ultimately cause and promote tumorigenesis.In normal tissues,the difference of energy demand may lead to differences in the copy number of mitochondrial DNA.However the copy number will be relatively stable in the same tissue,in order to maintain the normal physiological function.Mitochondrial DNA copy number can be regulated in two aspects by genetic and environmental factors,so its change to some extent reflects the influence of some factors,such as age,smoking,oxidative damage reaction and so on,which play a role on the occurrence and development of tumor cells and tissues,on the body.All of these prove that the mitochondrial DNA copy number may be a biomarker to predict cancer risk.At present,the relationship between mitochondrial DNA copy number in peripheral blood and the risk of different tumor have been discussed in many epidemiological studies,but these research conclusions are not consistent between themselves.There have been 5 articles reported the association between mitochondrial DNA copy number and the risk of head and neck squamous cell carcinoma and precancerous lesions,but the results of them was inconsistent.Therefore,it is necessary to conduct further study with large size of sample to confirm the relationship between mitochondrial DNA copy number and the risk of HNSCC.This study used a case-control design study to confirm the relationship between mitochondrial DNA copy number in peripheral blood and the risk of HNSCC.The cases were consisted of 570 new Patients of head and neck squamous cell carcinoma come from hospitals of Jiangsu area,when the 597 control samples were healthy individuals recruited from a community-based screening program for chronic disease,and were frequency-matched to cases based on age and sex.Mitochondrial DNA copy number was measured by quantitative PCR method.To be brief,mitochondrial DNA copy number was calculated based on the copy number measurement of mitochondrial gene(NADH dehydrogenase,subunit 1,ND1)and nuclear gene(hemoglobin subunit β,HGB)expressed as the ratio of ND1 and HGB threshold cycle numbers ratio in individual samples.In order to ensure the accuracy of detection of mitochondrial DNA copy number,each sample was arranged in parallel and repeated detection with blind method.The mean of measurements was used in the latter statistical analyses.Logistic regression model and restricted cubic spline function were used to analyze the relationship between mitochondrial DNA copy number and the risk of head and neck squamous cell carcinoma,and calculate the odds ratios(OR)and 95%confidence intervals(95%CI).As a result,mitochondrial DNA copy number in the cases(median:4.33,inter-quartile range:1.38-29.85)was significantly higher than that in controls(3.50,1.93-11.19,P=0.016).Mitochondrial DNA copy numbers were divided into four categories based on the quartile distribution of mitochondrial DNA copy number in controls in the order to examine the association between mitochondrial DNA copy number and HNSCC risk.The results showed a U-shaped relationship between the mitochondrial DNA copy number and the risk of HNSCC.Compared with those in the second quartile as reference,the adjusted odds ratios(95%CI)for individuals in the first and the forth quartile were 1.95(1.37-2.76)and 2.16(1.53-3.04),respectively.The U-shaped association remained significant in subgroups stratified by age,gender,tobacco smoking and alcohol consumption.What’s more,restricted cubic spline function also confirmed the U-shaped association.In this study,we discussed the association between mitochondrial DNA copy number and HNSCC risk,and found both extremely low and high mitochondrial DNA copy number were associated with an increased risk of HNSCC.The results in our study provided theoretical and technical support to screening and the prevention and control for HNSCC in high-risk population,and some clues for further studies in the the pathogenesis of head and neck squamous cell carcinoma.