Study on Mitochondrial ATPase6 Gene Polymorphisms as a Genetic Risk Factor for Breast Cancer in Bangladeshi Women

Document Type : Original Article

Authors

1 Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh

2 Centre for Advanced Research in Sciences (CARS), University of Dhaka, Dhaka-1000, Bangladesh

3 Bangladesh Reference Institute for Chemical Measurements, Dhaka-1205, Bangladesh

4 Department of Theoretical and Computational Chemistry, University of Dhaka, Dhaka-1000, Bangladesh

5 Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka-1000, Bangladesh

Abstract

Background and aim: Mitochondria play a vital role in cellular energy production and apoptosis; thus, it has a critical role in cancer development. This study aimed to evaluate polymorphisms in the mitochondrial ATPase6 gene as a genetic risk factor for breast cancer in Bangladeshi women.
Materials and method: ATPase6 gene of mtDNA from sixteen breast cancer blood samples were sequenced to evaluate polymorphisms in the targeted gene. Polymorphisms are detected by comparing the sequences with the Revised Cambridge Reference Sequence (rCRS). Twelve blood samples from age-matched healthy women were also sequenced as a control to consider regional variations.
Results: The A8812C polymorphism (p= 0.0085; from Fisher Exact Test) was found in 50% of breast cancer patients. The A8812C variation (novel mutation) substitutes the Threonine (T) to Proline (P) at the 96th codon number. The PolyPhen-2 analysis predicted that, with a score of 0.999, this variant is "probably damaging." The second prediction performed by the PROVEAN program showed that, since it has a score of -5,110 (<-2,5), this substitution is "Deleterious." These data indicate that A8812C might be associated with an increased risk of breast cancer indirectly. Another interesting finding is the frequent presence (56%) of A8701G in cancer patients (p= 0.0159; from Fisher Exact Test). Based on the statistical data, this (A8701G) mutation might relate to breast cancer development. 

Conclusion: It can be concluded that mutations in the ATPase6 gene, especially the A8812C polymorphism and A8701G polymorphism, can be biomarkers for breast cancer diagnosis.

Keywords

Main Subjects


[1] Nurun G, Sultana N, Rahman A, Din A, Shahinuzzaman A, Begum RA, et al. Mitochondrial DNA mutations-candidate biomarkers for breast cancer diagnosis in Bangladesh. Chin J Cancer. 2012;31(9):449–54. DOI: 10.5732/cjc.012.10024.
[2] Sariego J. Breast cancer in the young patient. The American surgeon.2010;76(12):1397-400. https://doi.org/10.1177/000313481007601226.
[3] Korde LA, Zujewski JA, Kamin L, Giordano S, Domchek S, Anderson WF, et al. Multidisciplinary meeting on male breast cancer: summary and research recommendations. Journal of Clinical Oncology. 2010;28(12):2114. doi: 10.1200/JCO.2009.25.5729.
[4] Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Nikšić M, et al. Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. The Lancet. 2018;391(10125):1023-75. https://doi.org/10.1016/S0140-6736(17)33326-3.
[5] Salas A, Yao YG, Macaulay V, Vega A, Carracedo A, Bandelt HJ. A critical reassessment of the role of mitochondria in tumorigenesis. PLoS Med. 2005;2(11):e296.
[6] Kong QP, Bandelt HJ, Sun C, Yao YG, Salas A, Achilli A, et al. Updating the East Asian mtDNA phylogeny: a prerequisite for the identification of pathogenic mutations. Human molecular genetics. 2006;15(13):2076-86. https://doi.org/10.1093/hmg/ddl130.
[7] HR FJ, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893-917. DOI:https://doi.org/10.1002/ijc.25516.
[8] Parrella P, Seripa D, Matera MG, Rabitti C, Rinaldi M, Mazzarelli P, et al. Mutations of the D310 mitochondrial mononucleotide repeat in primary tumors and cytological specimens. Cancer letters. 2003 Feb 10;190(1):73-7. DOI: https://doi.org/10.1016/S0304-3835(02)00578-5.
[9] Wu G, Xing M, Mambo E, Huang X, Liu J, Guo Z, et al. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast cancer research. 2005;7(5):1-8. https://doi.org/10.1186/bcr1262.
[10] Miyazono F, Schneider PM, Metzger R, Warnecke-Eberz U, Baldus SE, Dienes HP, et al. Mutations in the mitochondrial DNA D-Loop region occur frequently in adenocarcinoma in Barrett's esophagus. Oncogene. 2002;21(23):3780-3. https://doi.org/10.1038/sj.onc.1205532.
[11] Ghaffarpour M, Mahdian R, Fereidooni F, Kamalidehghan B, Moazami N, Houshmand M. The mitochondrial ATPase6 gene is more susceptible to mutation than the ATPase8 gene in breast cancer patients. Cancer cell international. 2014;14(1):1-9. https://doi.org/10.1186/1475-2867-14-21.
[12] Tiranti V. Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Granatiero M, et al. Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency. Am J Hum Genet. 1998;63:1609-21. DOI: https://doi.org/10.1086/302150.
[13] Holyoake AJ, McHugh P, Wu M, O'carroll S, Benny P, Sin IL, et al. High incidence of single nucleotide substitutions in the mitochondrial genome is associated with poor semen parameters in men. International journal of andrology. 2001;24(3):175-82. https://doi.org/10.1046/j.1365-2605.2001.00292.x.
[14] De Meirleir L, Seneca S, Lissens W, Schoentjes E, Desprechins B. Bilateral striatal necrosis with a novel point mutation in the mitochondrial ATPase 6 gene. Pediatric neurology. 1995;13(3):242-6. https://doi.org/10.1016/0887-8994(95)00184-H.
[15] Isohanni P, Carroll CJ, Jackson CB, Pohjanpelto M, Lönnqvist T, Suomalainen A. Defective mitochondrial ATPase due to rare mtDNA m. 8969G> A mutation—causing lactic acidosis, intellectual disability, and poor growth. neurogenetics. 2018;19(1):49-53. https://doi.org/10.1007/s10048-018-0537-9.
[16] Kumar R, Venkatesh S, Kumar M, Tanwar M, Shasmsi MB, Gupta NP, et al. Oxidative stress and sperm mitochondrial DNA mutation in idiopathic oligoasthenozoospermic men. 2009.
[17] Czarnecka AM, Krawczyk T, Zdrożny M, Lubiński J, Arnold RS, Kukwa W, et al. Mitochondrial NADH-dehydrogenase subunit 3 (ND3) polymorphism (A10398G) and sporadic breast cancer in Poland. Breast cancer research and treatment. 2010;121(2):511-8. https://doi.org/10.1007/s10549-009-0358-5.
[18] Amuthan G, Biswas G, Zhang SY, Klein‐Szanto A, Vijayasarathy C, Avadhani NG. Mitochondria‐to‐nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. The EMBO journal. 2001;20(8):1910-20. https://doi.org/10.1093/emboj/20.8.1910.
 [19] Matsuyama S, Xu Q, Velours J, Reed JC. The mitochondrial F0F1-ATPase proton pump is required for function of the proapoptotic protein Bax in yeast and mammalian cells. Molecular cell. 1998;1(3):327-36. https://doi.org/10.1016/S1097-2765(00)80033-7.
[20] Jakupciak JP, Dakubo GD, Maragh S, Parr RL. Analysis of potential cancer biomarkers in mitochondrial DNA. Current opinion in molecular therapeutics. 2006;8(6):500-6.
 [21] Modica-Napolitano JS, Kulawiec M, Singh KK. Mitochondria and human cancer. Current molecular medicine. 2007;7(1):121-31. DOI: https://doi.org/10.2174/156652407779940495.
[22] Wang Z, Choi S, Lee J, Huang YT, Chen F, Zhao Y, et al. Mitochondrial Variations in Non-Small Cell Lung Cancer (NSCLC) Survival: Supplementary Issue: Sequencing Platform Modeling and Analysis. Cancer informatics. 2015;14:CIN-S13976. https://doi.org/10.4137/CIN.S13976.
[23] Aikhionbare FO, Khan M, Carey D, Okoli J, Go R. Is cumulative frequency of mitochondrial DNA variants a biomarker for colorectal tumor progression?. Molecular Cancer. 2004;3(1):1-4. https://doi.org/10.1186/1476-4598-3-30.
[24] Houshmand M, Montazeri M, Kuchekian N, Noohi F, Nozar G, Zamani A. Is 8860 variation a rare polymorphism or associated as a secondary effect in HCM disease?. Archives of medical science: AMS. 2011;7(2):242. doi: 10.5114/aoms.2011.22074.
[25] Fauser S, Luberichs J, Besch D, Leo-Kottler B. Sequence analysis of the complete mitochondrial genome in patients with Leber's hereditary optic neuropathy lacking the three most common pathogenic DNA mutations. Biochemical and biophysical research communications. 2002;295(2):342-7. https://doi.org/10.1016/S0006-291X(02)00672-1.
[26] Mostafaie N, Rossmanith W, Hombauer H, Dechat T, Raffelsberger T, Bauer K, et al. Mitochondrial genotype and risk for Alzheimer’s disease: Cross-sectional data from the Vienna-Transdanube-Aging “VITA” study. Journal of neural transmission. 2004;111(9):1155-65. https://doi.org/10.1007/s00702-004-0161-8.
[27] Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annual Review of Pathology: Mechanisms of Disease. 2010;5:297-348.
[28] Wallace DC, Brown MD, Lott MT. Mitochondrial DNA variation in human evolution and disease. Gene. 1999;238(1):211-30. https://doi.org/10.1016/S0378-1119(99)00295-4.
[29] Grzybowska-Szatkowska L, Ślaska B, Rzymowska J, Brzozowska A, Floriańczyk B. Novel mitochondrial mutations in the ATP6 and ATP8 genes in patients with breast cancer. Molecular medicine reports. 2014;10(4):1772-8.
Volume 3, Issue 1
March 2021
Pages 18-22
  • Receive Date: 27 January 2021
  • Revise Date: 27 February 2021
  • Accept Date: 08 March 2021
  • First Publish Date: 08 March 2021