Associations of mitochondrial DNA copy number with incident risks of gastrointestinal cancers: a prospective case-cohort study

Abstract Background Epidemiological investigations implied that inter-individual variations of mitochondrial DNA copy number (mtDNAcn) could trigger predisposition to multiple cancers, but evidence regarding gastrointestinal cancers (GICs) was still uncertain. Methods We conducted a case-cohort study within the prospective Dongfeng-Tongji cohort, including incident cases of colorectal cancer (CRC, n=278), gastric cancer (GC, n=138), and esophageal cancer (EC, n=72) as well as a random subcohort (n=1173), who were followed up from baseline to the end of 2018. Baseline blood mtDNAcn was determined with quantitative PCR assay, and associations of mtDNAcn with the GICs risks were estimated by using weighted Cox proportional hazards models. Results Significant U -shaped associations were observed between mtDNAcn and risks of CRC, GC, EC, and total GICs. Compared to subjects within the 2 nd quartile (Q2) mtDNAcn subgroup, those within the 1 st (Q1), 3 rd (Q3) and 4 th (Q4) quartile subgroups showed increased risks of CRC [HR(95%CI)=2.27(1.47-3.52), 1.65(1.04-2.62), and 2.81(1.85-4.28), respectively] and total GICs [HR(95%CI)=1.84(1.30-2.60), 1.47(1.03-2.10), and 2.51(1.82-3.47), respectively], and those within Q4 subgroup present elevated GC and EC risks [HR(95%CI)=2.16(1.31-3.54) and 2.38(1.13-5.02), respectively]. Similar associations of mtDNAcn with CRC and total GICs risks remained in stratified analyzes by age, gender, and smoking status. Notably, there were joint effects of age and smoking status with mtDNAcn on CRC and total GICs risks. Conclusions This prospectively case-cohort study showed U -shaped associations between mtDNAcn and incident risks of GICs, but further researches are needed to confirm these results and uncover underlying biological mechanisms.