Molecular Biology Reports

, Volume 45, Issue 4, pp 591–600 | Cite as

Mitochondrial genome analysis in penile carcinoma

  • L. F. Araujo
  • A. T. TerraJr.
  • C. T. G. Sares
  • C. F. R. Sobreira
  • E. F. Faria
  • R. D. Machado
  • A. A. RodriguesJr.
  • V. F. Muglia
  • W. A. SilvaJr.
  • R. B. ReisEmail author
Original Article


Penile cancer is a rare neoplasm that seems to be linked to socio-economic differences. Mitochondrial genome alterations are common in many tumors types and are reported as regulating oxidative metabolism and impacting tumorigenesis. In this study, we evaluate for the first time the mitochondrial genome in penile carcinoma (PeCa), aiming to evaluate heteroplasmy, mitochondrial DNA (mtDNA) mutational load and mtDNA content in Penile tumors. Using next generation sequencing (NGS), we sequenced the mitochondrial genome of 13 penile tumors and 12 non-neoplastic tissue samples, which allowed us to identify mtDNA variants and heteroplasmy. We further evaluated variant’s pathogenicity using Mutpred predictive software and calculated mtDNA content using quantitative PCR. Mitochondrial genome sequencing revealed an increase number of non-synonymous variants in the tumor tissue, along with higher frequency of heteroplasmy and mtDNA depletion in penile tumors, suggesting an increased mitochondrial instability in penile tumors. We also described a list of mitochondrial variants found in penile tumor and normal tissue, including five novel variants found in the tumoral tissue. Our results showed an increased mitochondrial genome instability in penile tumors. We also suggest that mitochondrial DNA copy number (mtDNAcn) and mtDNA variants may act together to imbalance mitochondrial function in PeCa. The better understanding of mitochondrial biology can bring new insights on mechanisms and open a new field for therapy in PeCa.


Mitochondrial genome Penile carcinoma Mutation MtDNA copy number Heteroplasmy 



We would like to thank Anemari Dinarti-Santos for technical support.


This study was funded by São Paulo Research Foundation (FAPESP), Grants #2009/53853-5, #2013/25119-0, and #2013/08135-2; and by Research Support of the University Sao Paulo, CISBi-NAP/USP Grant #12.1.25441.01.2.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest in the authorship or publication of contribution.

Ethical approval

This study was previously approved by the Ethics Committee of Ribeirão Preto at University of São Paulo (Process Number 14096/2010). All patients gave their written consent to participate in this study.

Supplementary material

11033_2018_4197_MOESM1_ESM.xlsx (32 kb)
Supplementary material 1 (XLSX 32 KB)
11033_2018_4197_MOESM2_ESM.docx (116 kb)
Supplementary material 2 (DOCX 115 KB)


  1. 1.
    Bleeker MCG, Heideman DAM, Snijders PJF et al (2008) Penile cancer: epidemiology, pathogenesis and prevention. World J Urol 27:141–150. CrossRefPubMedGoogle Scholar
  2. 2.
  3. 3.
    INCA (2017) Estimativas de Câncer 2016. In: Accessed 6 Jun 2017
  4. 4.
    Daling JR, Madeleine MM, Johnson LG et al (2005) Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer 116:606–616. CrossRefPubMedGoogle Scholar
  5. 5.
    Dillner J, Krogh von G, Horenblas S, Meijer CJLM. (2009) Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol 34:189–193. CrossRefGoogle Scholar
  6. 6.
    Ali SM, Pal SK, Wang K et al (2016) Comprehensive genomic profiling of advanced penile carcinoma suggests a high frequency of clinically relevant genomic alterations. Oncologist 21:33–39. CrossRefPubMedGoogle Scholar
  7. 7.
    Kuasne H, de Syllos Cólus IM, Busso AF et al (2015) Genome-wide methylation and transcriptome analysis in penile carcinoma: uncovering new molecular markers. Clin Epigenetics 7(1):46. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kuasne H, Barros-Filho MC, Busso-Lopes A et al (2017) Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact. Oncotarget 8:15294–15306. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Reznik E, Miller ML, Şenbabaoğlu Y et al (2016) Mitochondrial DNA copy number variation across human cancers. eLife 5:e10769. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Yu M (2011) Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. Life Sci 89:65–71CrossRefPubMedGoogle Scholar
  11. 11.
    Ghelli A, Tropeano CV, Calvaruso MA et al (2013) The cytochrome b p. 278Y> C mutation causative of a multisystem disorder enhances superoxide production and alters supramolecular interactions of respiratory chain complexes. Hum Mol Genet 22:2141–2151. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hardie R-A, van Dam E, Cowley M et al (2017) Mitochondrial mutations and metabolic adaptation in pancreatic cancer. Cancer Metab 5(1):2. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Iommarini L, Calvaruso MA, Kurelac I et al (2013) Complex I impairment in mitochondrial diseases and cancer: parallel roads leading to different outcomes. Int J Biochem Cell Biol 45:47–63. CrossRefPubMedGoogle Scholar
  14. 14.
    Ishikawa K, Takenaga K, Akimoto M et al (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320:661–664. CrossRefPubMedGoogle Scholar
  15. 15.
    de Araujo LF, Fonseca AS, Muys BR et al (2015) Mitochondrial genome instability in colorectal adenoma and adenocarcinoma. Tumour Biol 36:8869–8879. CrossRefPubMedGoogle Scholar
  16. 16.
    Pejaver V, Urresti J, Lugo-Martinez J et al (2017) MutPred2: inferring the molecular and phenotypic impact of amino acid variants. bioRxiv. CrossRefGoogle Scholar
  17. 17.
    Lott MT, Leipzig JN, Derbeneva O et al (2013) mtDNA variation and analysis using MITOMAP and MITOMASTER. Curr Protoc Bioinform 44:1–23. CrossRefGoogle Scholar
  18. 18.
    Venegas V, Wang J, Dimmock D, Wong LJ (2011) Real-time quantitative PCR analysis of mitochondrial DNA content. 72:101–119.
  19. 19.
    Ju YS, Alexandrov LB, Gerstung M et al (2014) Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. eLife 3:415–454. CrossRefGoogle Scholar
  20. 20.
    Mullen AR, Hu Z, Shi X et al (2014) Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep 7:1679–1690. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Singh RK, Srivastava A, Kalaiarasan P et al (2014) mtDNA germ line variation mediated ROS generates retrograde signaling and induces pro-cancerous metabolic features. Sci Rep 4:6571. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ji Y, Liang M, Zhang J et al (2016) Mitochondrial ND1 variants in 1281 Chinese subjects with Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 57:2377–2389. CrossRefPubMedGoogle Scholar
  23. 23.
    Sciacco M, Prelle A, Fagiolari G et al (2005) A case of CPT deficiency, homoplasmic mtDNA mutation and ragged red fibers at muscle biopsy. J Neurol Sci 239:21–24. CrossRefPubMedGoogle Scholar
  24. 24.
    Gerbitz KD, van den Ouweland JM, Maassen JA, Jaksch M (1995) Mitochondrial diabetes mellitus: a review. Biochim Biophys Acta 1271:253–260CrossRefPubMedGoogle Scholar
  25. 25.
    Jerónimo C, Nomoto S, Caballero OL et al (2001) Mitochondrial mutations in early stage prostate cancer and bodily fluids. Oncogene 20:5195–5198. CrossRefPubMedGoogle Scholar
  26. 26.
    Zhang J, Zhou X, Zhou J et al (2010) Mitochondrial ND6 T14502C variant may modulate the phenotypic expression of LHON-associated G11778A mutation in four Chinese families. Biochem Biophys Res Commun 399:647–653. CrossRefPubMedGoogle Scholar
  27. 27.
    Abu-Amero KK, Bosley TM (2006) Mitochondrial abnormalities in patients with LHON-like optic neuropathies. Invest Ophthalmol Vis Sci 47:4211–4220. CrossRefPubMedGoogle Scholar
  28. 28.
    Ye K, Lu J, Ma F et al (2014) Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals. Proc Natl Acad Sci USA 111:10654–10659. CrossRefPubMedGoogle Scholar
  29. 29.
    Stefano G, Kream R (2016) Mitochondrial DNA heteroplasmy in human health and disease. Biom Rep. CrossRefGoogle Scholar
  30. 30.
    Zhang G, Frederick DT, Wu L et al (2016) Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. J Clin Invest 126:1834–1856. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • L. F. Araujo
    • 1
    • 2
  • A. T. TerraJr.
    • 3
  • C. T. G. Sares
    • 3
  • C. F. R. Sobreira
    • 4
  • E. F. Faria
    • 5
  • R. D. Machado
    • 5
  • A. A. RodriguesJr.
    • 3
  • V. F. Muglia
    • 6
  • W. A. SilvaJr.
    • 1
    • 2
    • 7
  • R. B. Reis
    • 3
    • 7
    • 8
    Email author
  1. 1.Department of Genetics at Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil
  2. 2.National Institute of Science and Technology in Stem Cell and Cell Therapy, and Center for Cell-based Therapy-CEPID/FAPESPRibeirão PretoBrazil
  3. 3.Hospital das Clinicas, Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil
  4. 4.Department of Neuroscience, Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil
  5. 5.Department of UrologyBarretos Cancer HospitalBarretosBrazil
  6. 6.Center of Imaging Sciences and Medical Physics, Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil
  7. 7.Center for Medical Genomics, HCFMRP/USP, and Center for Integrative System Biology - CISBi-NAP/USPUniversity of São PauloRibeirão PretoBrazil
  8. 8.Division of Urology, Department of Surgery, Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil

Personalised recommendations