Correlational study on mitochondrial DNA mutations as potential risk factors in breast cancer

Abstract

The presented study performed an mtDNA genome-wide association analysis to screen the peripheral blood of breast cancer patients for high-risk germline mutations. Unlike previous studies, which have used breast tissue in analyzing somatic mutations, we looked for germline mutations in our study, since they are better predictors of breast cancer in high-risk groups, facilitate early, non-invasive diagnoses of breast cancer and may provide a broader spectrum of therapeutic options. The data comprised 22 samples of healthy group and 83 samples from breast cancer patients. The sequencing data showed 170 mtDNA mutations in the healthy group and 393 mtDNA mutations in the disease group. Of these, 283 mtDNA mutations (88 in the healthy group and 232 in the disease group) had never been reported in the literature. Moreover, correlation analysis indicated there was a significant difference in 32 mtDNA mutations. According to our relative risk analysis of these 32 mtDNA mutations, 27 of the total had odds ratio values (ORs) of less than 1, meaning that these mutations have a potentially protective role to play in breast cancer. The remaining 5 mtDNA mutations, RNR2-2463 indelA, COX1-6296 C>A, COX1-6298 indelT, ATP6-8860 A>G, and ND5-13327 indelA, whose ORs were 8.050, 4.464, 4.464, 5.254 and 4.853, respectively, were regarded as risk factors of increased breast cancer. The five mutations identified here may serve as novel indicators of breast cancer and may have future therapeutic applications. In addition, the use of peripheral blood samples was procedurally simple and could be applied as a non-invasive diagnostic technique.

A family case with germlineTSC1and mtDNA mutations developing bilateral eosinophilic chromophobe renal cell carcinomas without other typical phenotype of tuberous sclerosis

“…A previous study reported 170 mtDNA mutations in 22 samples from a healthy cohort,21 and the average frequency of mtDNA germline mutations was similar to our results. Three mtDNA mutations in the present cases were observed in mitochondrial haplogroup D4f1.…”

Correlation study on mtDNA polymorphisms as potential risk factors in aggressive periodontitis by NGS

“…One of the most widely studied mitochondrial SNPs is G10398A. Related studies reported that 10398A was associated with some systemic diseases, increasing the risk of Parkinson's disease, breast cancer, and other types (Chia‐Wei et al, ; Gui et al, ; Juo et al, ; Li et al, ; Mims et al, ; van der Walt et al, ). A recent study showed that cognitive decline was not related to any usual risk factor but to the G allele of A10398G in mtDNA (Monte et al, ), and another study suggested that the mitochondrial DNA 10398 A/G polymorphism plays a possible role in the genetic etiology of attention deficit hyperactivity disorder (ADHD) in Korean children (Hwang et al, ).…”

“…The clinical phenotypes associated with the G8701A polymorphism have been reported to include hereditary optic neuropathy, mitochondrial encephalomyopathy, Parkinson's syndrome, deafness, and metabolic syndrome; of these, deafness was identified in a pedigree study (Chalkia et al, ; Li, Zhang, Li, & Wang, ; Martikainen et al, ; Mkaouar‐Rebai, Tlili, Masmoudi, Charfeddine, & Fakhfakh, ). The A8860G polymorphism has been detected in many diseases, but evidence for its association with these diseases is not strong (Bahreini, Houshmand, Modarressi, & Akrami, ; Chia‐Wei et al, ; Li et al, , ; Masserrat et al, ). Some authors found that A8860G may reduce the stability of ATPase6 (Houshmand et al, ), but another study suggested that it is a benign point mutation with no effect on protein function (Masserrat et al, ).…”

“…A Chinese pedigree study found that mitochondrial dysfunction caused by the A8701G polymorphism may promote the pathophysiology of cardiovascular disease alone or synergistically (Zhu, Gu, & Xu, 2016 (Chalkia et al, 2018;Li, Zhang, Li, & Wang, 2014;Martikainen et al, 2013;Mkaouar-Rebai, Tlili, Masmoudi, Charfeddine, & Fakhfakh, 2008). The A8860G polymorphism has been detected in many diseases, but evidence for its association with these diseases is not strong (Bahreini, Houshmand, Modarressi, & Akrami, 2018;Chia-Wei et al, 2012;Li et al, 2016Li et al, , 2014Masserrat et al, 2018). Some authors found that A8860G may reduce the stability of ATPase6 (Houshmand et al, 2011), but another study suggested that it is a benign point mutation with no effect on protein function (Masserrat et al, 2018).…”

Single nucleotide mtDNA polymorphisms may contribute to cancerogenesis in mitochondrial disorders

“…A pro-oncogenic state may not only be favored by mtDNA mutations or the haplotype but also by mtDNA polymorphisms. This has been shown for single nucleotide polymorphisms (SNPs) in the D-loop (colorectal adenoma) [Thyagarajan et al, in press], the tRNA(Ile) gene (colorectal cancer) [Kumar et al, 2017], COX genes (hepatocellular carcinoma) [Wang et al, in press], and in COX1, COX2, ND5, and ATP6 genes respectively (breast cancer) [Li et al, 2016].…”