CYTB: A HOT SPOT FOR PATHOGENIC MUTATIONS IN MITOCHONDRIAL GENOME OF BREAST CANCER AND OVARIAN CANCER PATIENTS
Keywords:
Mitochondrial subunits, Mutations, In-silico, OXPHOS, Breast cancer (BC), Ovarian cancer (OC)Abstract
Objective: Out of various cancer types, Breast and ovarian cancers are the most commonly occurring malignancies in women. As per literature, a large number of mutations are reported in various mitochondrial genome encoded subunits of respiratory chain complexes in breast and ovarian cancer patients. However, a very few of them are functionally validated till now. Our study is an attempt to highlight the pathogenic potential of all these reported mutations in breast and ovarian cancer patients.
Methods: In order to achieve so, total 109mitochondrial gene mutations of breast cancer and 11 mitochondrial gene mutations of ovarian cancer patients were selected from MITOMAP database as well as various literatures. All these mutations were analyzed using various in silico tools such as MUSCLE, PolyPhen-2, SIFT, Mut Pred, Mu Pro, PANTHER, GOR4 and MUSCLE.
Results: As a result of our analysis, 28 out 95 mutations in CytB gene are most pathogenic in the case of breast cancer patients. On the other hand 2 out of 3 mutations of the same gene were predicted to be potentially pathogenic in case of ovarian cancer patients. Mutations in other mitochondrial subunit was also predicted pathogenic but with the low score.
Conclusion: Out of different mitochondrial subunits, CytB seems to most important site for mutations in these two groups of patients. Hence, mutations of CytB subunit, which are predicted to be highly pathogenic as per our analysis, should be functionally validated in future.
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References
Chan DC. Mitochondria: dynamic organelles in disease, aging and development. Cell 2006;125:1241-52.
Attardi G, Schatz G. Biogenesis of mitochondria. Annu Rev Cell Biol 1988;4:289–333.
Rohan TE, Wang T, Kabat GC, Wong LJ, Haines J. Do Alterations in mitochondrial DNA play a role in breast carcinogenesis? J Oncol 2010;1-11. doi: 10.1155/2010/604304. [Article in Press]
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 2008;7:11-20.
Gogvadze V, Zhivotovsky B, Orrenius S. The Warburg effect and mitochondrial stability in cancer cells. Mol Aspects Med 2010;31:60-74.
Carew JS, Huang P. Mitochondrial defects in cancer. Mol Cancer 2002;9:1-9.
Greaves LC, Reeve AK, Taylor RW, Turnbull DM. Mitochondrial DNA and disease. J Pathol 2012;226:274–86.
Sullivan LB, Chandel NS. Mitochondrial reactive oxygen species and cancer. Cancer Metab 2014;2:17.
Weigl S, Paradiso A, Tommasi S. Mitochondria and familial predisposition to breast cancer. Curr Genomics 2013;14:195–203.
http://writetribe.com/world-cancer-day-2014/. [Last accessed on 04 Feb 2014].
World Health Organization. Breastcancer: prevention and control. Available from: URL: http://www.who.int cancer/ detection/breastcancer/en/index1.html#. [Last accessed on 04 Feb 2014].
Ovarian Cancer Prevention (PDQ®). National Cancer Institute; 2013. Available from: URL: http://www.cancer.gov/ cancertopics/pdq/prevention/ovarian/healthprofessional. [Last accessed on 30 Dec 2013].
World Health Organization. WHO Disease and injury country estimates; 2009. Available from: URL: http://www.who.int/ healthinfo/global_burden_disease/estimates_country/en/. [Last accessed on 11 Nov 2009].
Fendt L, Niederstätter H, Huber G, Zelger B, Dünser M, Seifarth C, et al. Accumulation of mutations over the entire mitochondrial genome of breast cancer cells obtained by tissue microdissection. Breast Cancer Res Treat 2011;128:327-36.
Petsko GA, Ringe D. Protein structure and function. New Science Press; 2004.
Betts MJ, Russell RB. Amino acid properties and consequences of substitutions. Bioinf Genet 2003;317:289.