The saga of the many studies wrongly associating mitochondrial DNA with breast cancer

Abstract

BackgroundA large body of genetic research has focused on the potential role that mitochondrial DNA (mtDNA) variants might play on the predisposition to common and complex (multi-factorial) diseases. It has been argued however that many of these studies could be inconclusive due to artifacts related to genotyping errors or inadequate design.MethodsAnalyses of the data published in case–control breast cancer association studies have been performed using a phylogenetic-based approach. Variation observed in these studies has been interpreted in the light of data available on public resources, which now include over >27,000 complete mitochondrial sequences and the worldwide phylogeny determined by these mitogenomes. Complementary analyses were carried out using public datasets of partial mtDNA sequences, mainly corresponding to control-region segments.ResultsBy way of example, we show here another kind of fallacy in these medical studies, namely, the phenomenon of SNP-SNP interaction wrongly applied to haploid data in a breast cancer study. We also reassessed the mutually conflicting studies suggesting some functional role of the non-synonymous polymorphism m.10398A > G (ND3 subunit of mitochondrial complex I) in breast cancer. In some studies, control groups were employed that showed an extremely odd haplogroup frequency spectrum compared to comparable information from much larger databases. Moreover, the use of inappropriate statistics signaled spurious “significance” in several instances.ConclusionsEvery case–control study should come under scrutiny in regard to the plausibility of the control-group data presented and appropriateness of the statistical methods employed; and this is best done before potential publication.

Mitochondrial DNA Haplogroup A Decreases the Risk of Drug Addiction but Conversely Increases the Risk of HIV-1 Infection in Chinese Addicts

“…[23][24][25]). In this study, we have attempted to show whether the mtDNA haplogroup of a person confers a genetic susceptibility to drug addiction and HIV-1 infection in Chinese individuals from Southwest China.…”

“…However, a number of these studies had a high incidence of false positive associations due to various errors, and rigorous methodological and statistical standards in mtDNA genetic association studies should be performed to avoid any false positive associations between mtDNA variants and neurological diseases or between mtDNA variants and cancer (cf. [23][24][25]). We hypothesize that the inherited mtDNA haplogroup may affect the risk of drug addiction and the subsequent risk of acquiring HIV-1 infection.…”

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

“…In a study performed by Mosquera-Miguel et al also no association was found for this variation in a Spanish population [121]. Recently, Salas et al reanalyzed all studies and no correlation could be found regarding the m.10398A>G SNP [122].…”

Breast cancer‐associated mitochondrial DNA haplogroup promotes neoplastic growth via ROS‐mediated AKT activation

“…Due to in‐proper use of statistical methods and some other questionable issues in previous published works, a reassessment of mtDNA haplogroups in the occurrence of breast cancer was made recently . In our previous study, we found that haplogroup D5, which is a sub‐haplogroup of the M macro‐haplogroup, had a significantly higher frequency in patients with breast cancer compared to that found in control subjects ( p = 0.03) .…”

“…In the past decade, multiple mtDNA haplogroups were identified and associated with breast cancer in different populations . Previously, haplogroup D5 was found to be a risk factor for multiple cancer types including breast cancer, although other studies found that D5 did not significantly contribute to predisposition to prostate cancer or breast cancer . To address these contradictory findings, and to better understand whether haplogroup D5 has a role in cancer occurrence, and in particular breast cancer, we aimed to elucidate the role of mtDNA haplogroup D5 in breast cancer at both the genetic and molecular levels using a case‐control study with a large cohort of women with breast cancer from Southern China and functional analyses using trans‐mitochondrial approaches.…”