Abstract
Mitochondrial common variants (mtSNPs) and the haplogroups defined by them have been inconsistently correlated with increased prostate cancer risk. Here we aimed to investigate the influence of the mitochondrial genetic background on prostate cancer. A total of 15 single-nucleotide polymorphisms (SNPs) representing the common European branches of the mtDNA phylogeny were analyzed in a cohort of 620 Spanish prostate cancer patients and 616 matched population-based controls. Association tests were computed on mtSNPs and haplogroups. None of the evaluated mtSNPs or haplogroups were statistically associated with prostate cancer risk in our Spanish cohort. We show that previous association findings do not rest on solid grounds given that all of them (i) were based on underpowered studies, (ii) did not control for population stratification, (iii) lacked replication/confirmation cohorts, and (iv) and did not control for multiple test corrections. Taken together, a critical reassessment of the previous literature and the results obtained in the present study suggest that mtDNA common European variants are not correlated with increases in the risk for prostate cancer.
Similar content being viewed by others
Introduction
Mitochondrial germline DNA variation has been suggested as a marker of susceptibility to numerous types of cancer given the role of mitochondria as the major source of reactive oxygen species production and as part of the apoptosis system. Several studies have inconsistently reported an association between DNA single-nucleotide polymorphisms (mtSNPs) and common haplogroups with prostate cancer susceptibility.1, 2, 3, 4, 5, 6, 7 Here we aimed to (i) assess the potential pathogenic role of well-known mtDNA variants, and the haplogroups defined by these mtSNPs, in the risk of developing prostate cancer and (ii) validate positive associated mtSNPs identified in cohorts of prostate cancer patients by others.
Materials and methods
Study subjects
Samples were obtained from 620 unselected consecutive Galician (NW Spain) prostate cancer patients, treated as previously described.8 The data have been generated previously and analyzed in the context of radio-induced therapy.9 Clinical characteristics of the patients are summarized in Table 1. We have now carried out a case–control study of these prostate cancer patients with an ethnically matched Spanish group that consisted of 616 individuals; these controls corresponded to the CG2 group analyzed previously.10
Written informed consent was obtained for each subject according to the protocols approved by the ethics review board of the Galician Ethical Committee for Clinical Research and in compliance with the declaration of Helsinki principles.
mtSNP selection and genotyping
mtDNA SNP selection was carried out as in the study by Salas et al.10 A set of 15 mtSNPs representing the most common European branches of the phylogeny were genotyped as described in the study by Cerezo et al.11 mtDNA haplotypes were phylogenetically checked following the methodology reported by Salas and colleagues.12 Figure 1 in the study by Fachal et al.9 shows the phylogeny that indicates the correspondence between the mtSNPs analyzed in the present study and the main European haplogroups they represent.
Statistical analysis
Association analyses for individual mtSNPs as well as for individual haplogroups with prostate cancer were performed using a one-degree of freedom Pearson’s χ2-test or, when appropriate, Fisher’s exact test. Statistical analyses were carried out using R v2.15.2 (http://www.r-project.org/). MitPower13 (http://bioinformatics.cesga.es/mitpower/) was used for estimation of the statistical power. Meta-analysis of haplogroup U results was carried out with the R library meta, using fixed- and random-effects models and the inverse variance method for pooling the effects (odds ratios) observed in each study.
Results
Association tests were carried out individually for mtSNPs and mtDNA haplogroups (Table 2). We did not find a statistically significant association between haplogroup and mtSNP distribution in prostate cancer patients compared with the control group. The statistical power to detect increases in prostate cancer risk higher than 1.75 was 83.1 (Figure 1). It is important to note that the present work showed the highest statistical power among the different studies published to date on prostate cancer and mtDNA variants (Table 3). The results of the meta-analysis carried out on haplogroup U are shown in Figure 2. Statistically significant heterogeneity between the studies was observed (I2=0.62, P-value=0.022). However, no association between haplogroup U and prostate cancer risk could be observed with any of the models used (fixed effects P-value=0.32, random effects P-value=0.21).
Discussion
The aim of the present study was to evaluate the influence of mtSNPs and haplogroups in prostate carcinogenesis by means of a case–control study involving 1236 individuals. Previous mtDNA association studies on prostate cancer have shown contradictory findings.1, 2, 3, 4, 5, 6, 7 Three of them showed positive associations. Ray et al.2 indicated the association of T6221C and T7389C mtSNPs in prostate cancer, whereas Booker et al.4 and Canter et al.6 showed the association of haplogroup U. Note, however, that these three studies were underpowered when considering odds ratio values ⩽2 (Table 3). Besides, none of these positive studies provides control for multiple testing (with the exception of the study by Canter et al.,6 in which only one mtSNP was evaluated). We investigated the literature for other prostate cancer studies in which these SNPs and haplogroups were tested and found four studies indicating the lack of association between haplogroup U and prostate cancer.1, 3, 5, 7 However, apart from the study by Wang et al.,7 none of the other three studies are powered enough to detect at least twofold increases in risk. In order to increase the power to detect a putative effect of haplogroup U in prostate cancer risk we have meta-analyzed the results from previous studies. No statistical significance was observed. Regarding associated mtSNPs from the study by Ray et al.,2 to our knowledge, neither T6221C nor T7389C mtSNP was interrogated in relation to prostate cancer susceptibility by other studies.
Among the limitations of our study is the fact that we have analyzed 15 mtSNPs signaling well-known European haplogroups, and therefore we cannot exclude the possibility of other variations being associated with prostate cancer risk. For instance, we did not explore variation within some of the main haplogroups tested in the present study (see Phylotree Build 16 for a refined version of the worldwide mtDNA phylogeny; www.phylotree.org); some of them are also frequent in the Spanish population. Furthermore, our study is not powered enough (that is, above 80%) to detect increases in risk lower than 1.75.
In summary, we did not observe statistical association between the mtDNA variants and haplogroups tested in our study with prostate cancer. Our study confirms other’s findings (although underpowered) suggesting that haplogroup U is not associated with prostate cancer (at least considering a moderate risk increase above 1.75). We have also commented on some statistical/methodological issues that could explain spurious positive findings in the literature on prostate cancer.
References
Mueller, E. E., Eder, W., Mayr, J. A., Paulweber, B., Sperl, W., Horninger, W. et al. Mitochondrial haplogroups and control region polymorphisms are not associated with prostate cancer in middle European Caucasians. PLoS ONE 4, e6370 (2009).
Ray, A. M., Zuhlke, K. A., Levin, A. M., Douglas, J. A., Cooney, K. A. & Petros, J. A. Sequence variation in the mitochondrial gene cytochrome c oxidase subunit I and prostate cancer in African American men. Prostate 69, 956–960 (2009).
Kim, W., Yoo, T. K., Shin, D. J., Rho, H. W., Jin, H. J., Kim, E. T. et al. Mitochondrial DNA haplogroup analysis reveals no association between the common genetic lineages and prostate cancer in the Korean population. PLoS ONE 3, e2211 (2008).
Booker, L. M., Habermacher, G. M., Jessie, B. C., Sun, Q. C., Baumann, A. K., Amin, M. et al. North American white mitochondrial haplogroups in prostate and renal cancer. J. Urol. 175, 468–473 (2006).
Álvarez-Cubero, M. J., Saiz Guinaldo, M., Martínez-González, L. J., Álvarez Merino, J. C., Cózar Olmo, J. M. & Acosta, J. A. L. Mitochondrial haplogroups and polymorphisms reveal no association with sporadic prostate cancer in a southern European population. PLoS ONE 7, e41201 (2012).
Canter, J. A., Kallianpur, A. R. & Fowke, J. H. Re: North American white mitochondrial haplogroups in prostate and renal cancer: L. M. Booker, G. M. Habermacher, B. C. Jessie, Q. C. Sun, A. K. Baumann, M. Amin, S. D. Lim, C. Fernandez-Golarz, R. H. Lyles, M. D. Brown, F. F. Marshall and J. A. Petros J Urol, 175: 468–473, 2006. J. Urol. 176, 2308–2309 (2006).
Wang, L., McDonnell, S. K., Hebbring, S. J., Cunningham, J. M. St, Sauver, J., Cerhan, J. R. et al. Polymorphisms in mitochondrial genes and prostate cancer risk. Cancer Epidemiol. Biomarkers Prev. 17, 3558–3566 (2008).
Fachal, L., Gómez-Caamaño, A., Peleteiro, P., Carballo, A., Calvo-Crespo, P., Sánchez-García, M. et al. Association of a XRCC3 polymorphism and rectum mean dose with the risk of acute radio-induced gastrointestinal toxicity in prostate cancer patients. Radiother. Oncol. 105, 321–328 (2012).
Fachal, L., Mosquera-Miguel, A., Gómez-Caamano, A., Sánchez-Garcia, M., Calvo, P., Lobato-Busto, R. et al. Evaluating the role of mitochondrial DNA variation to the genetic predisposition to radiation-induced toxicity. Radiother. Oncol. (e-pub ahead of print 16 April 2014; doi:10.1016/j.radonc.2014.03.012)..
Salas, A., Fachal, L., Marcos-Alonso, S., Vega, A., Martinón-Torres, F. & Grupo de investigación, E. Investigating the role of mitochondrial haplogroups in genetic predisposition to meningococcal disease. PLoS ONE 4, e8347 (2009).
Cerezo, M., Černý, V., Carracedo, Á. & Salas, A. Applications of MALDI-TOF MS to large-scale human mtDNA population-based studies. Electrophoresis 30, 3665–3673 (2009).
Salas, A., Yao, Y. G., Macaulay, V., Vega, A., Carracedo, Á. & Bandelt, H. J. A critical reassessment of the role of mitochondria in tumorigenesis. PLoS Med. 2, e296 (2005).
Pardo-Seco, J., Amigo, J., González-Manteiga, W. & Salas, A. A generalized model to estimate the statistical power in mitochondrial disease studies involving 2 × k tables. PLoS ONE 8, e73567 (2013).
Acknowledgements
This work was funded by a grant from the Instituto de Salud Carlos III (FIS PI10/00164), Fondo Europeo de Desarrollo Regional (FEDER 2007–2013), given to A.V., and grants from the ‘Ministerio de Ciencia e Innovación’ (SAF2011-26983 and PI13/02030) and from the Plan Galego IDT, Xunta de Galicia (EM 2012/045), given to A.S. L.F. is supported by the Isabel Barreto program from Xunta de Galicia and Fondo Social Europeo. We are grateful to all participating patients for their cooperation. We thank the Spanish National Genotyping Center CeGen (http://www.cegen.org/) for providing the single-nucleotide polymorphism genotyping services.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Fachal, L., Gómez-Caamaño, A., Álvarez Iglesias, V. et al. No association between typical European mitochondrial variation and prostate cancer risk in a Spanish cohort. J Hum Genet 59, 411–414 (2014). https://doi.org/10.1038/jhg.2014.46
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/jhg.2014.46