Skip to main content

Advertisement

Log in

Breast Cancer Risk Associated with Genotype Polymorphisms of the Aurora Kinase a Gene (AURKA): a Case-Control Study in a High Altitude Ecuadorian Mestizo Population

  • Original Article
  • Published:
Pathology & Oncology Research

An Erratum to this article was published on 05 September 2017

This article has been updated

Abstract

Breast cancer (BC) is the leading cause of cancer related death among women in 2014. The AURKA gene that encodes the protein called Aurora kinase A plays an important role in the progression of the cell cycle, by controlling and promoting the entry into the phase of mitosis. The single nucleotide polymorphism AURKA T91A (rs2273535) (Phe21Ile) has been identified as functional alternator of this kinase, the Ile allele is associated with the occurrence of chromosome segregation errors and tumor progression. Therefore, it is essential to know how BC risk is associated with histopathological characteristics, immunohistochemical characteristics, and genotype polymorphism in a high altitude Ecuadorian mestizo population. In this retrospective case-control study 200 individuals were analyzed. DNA was extracted from 100 healthy and 100 affected women. Genotypes were determined by genomic sequencing. We found significant association between the AURKA T91A (rs2273535) (Phe21Ile) genotype and an increased risk of BC development: Phe/Ile (odds ratio [OR] = 2.6; 95% confidence interval [CI] = 1.4–4.9; P = 0.004), Ile/Ile (OR = 3.8; 95% CI = 1.6–9.0; P = 0.002), and Phe/Ile + Ile/Ile (OR = 2.9; 95% CI = 1.6–5.2; P = 0.001). Additionally, the rs2273535 variant was associated with the tumor grade SBR III (OR = 9.6; 95% CI = 1.0–91.9; P = 0.048) and the Ki-67 ≥ 20 (OR = 16.5; 95% CI = 2.7–101.3; P = 0.002). In brief, this study provides the first evidence where the Ile allele of the AURKA gene could act as potentially predictive biomarker of BC in the high altitude Ecuadorian mestizo population that lives at 2800 m above sea level (masl).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Change history

  • 05 September 2017

    An erratum to this article has been published.

References

  1. Cancer Research UK. Worldwide cancer statistics. In: Cancer statistics. 2014. www.cancerresearchuk.org/cancer info/cancerstats/world. Accessed 7 Nov 2014

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  3. World Health Organization. International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. 2012. http://globocan.iarc.fr/ Default.aspx. Accessed 7 Nov 2016

  4. Kumar V, Abbas A, Aster J. (2012) Robbins basic pathology. 9th ed. Philadelphia: Saunders

  5. National Cancer Institute at the National Institutes of Health (2014) Histopathologic classification of breast cancer. In: Breast cancer treatment. http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page2. Accessed 7 Nov 2014

  6. Kumar R, Sharma A, Tiwari R (2012) Application of microarray in breast cancer: an overview. J Pharm Bioallied Sci 4:21–26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Banerji S, Cibulskis K, Rangel-Escareno C, Brown K, Carter S, Frederick A, Lawrance M, Sivachenko A, Sougnez C, Zou L, Cortes M, Fernandez-Lopez J, Peng S, Ardlie K, Auclair D, Bautista-Piña V, Duke F, Francis J, Jung J, Maffuz-Aziz A, Onofrio R, Parkin M, Pho N, Quintanar-Jurado V, Ramos A, Rebollar-Vega R, Rodriguez-Cuevas S, Romero-Cordoba S, Schumacher S, Stransky N, Thompson K, Uribe-Figueroa L, Baselga J, Beroukhim R, Polyak K, Sgroi D, Richardson A, Jimenez-Sanchez G, Lander E, Gabriel S, Garraway L, Golub T, Melendez-Zajgla J, Toker A, Getz G, Hidalgo-Miranda A, Meyerson M (2012) Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486:405–409

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Eisenstein M (2015) Startups use short-read data to expand long-read sequencing market. Nat Biotechnol 33:433–435

    Article  PubMed  CAS  Google Scholar 

  9. Wong KM, Hudson TJ, McPherson JD (2011) Unraveling the genetics of cancer: genome sequencing and beyond. Annu Rev Genomics Hum Genet 12:407–430

    Article  PubMed  CAS  Google Scholar 

  10. Meyerson M, Gabriel S, Getz G (2010) Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet 11:685–696

    Article  PubMed  CAS  Google Scholar 

  11. Eifert C, Powers RS (2012) From cancer genomes to oncogenic drivers, tumour dependencies and therapeutic targets. Nat Rev Cancer 12:572–578

    Article  PubMed  CAS  Google Scholar 

  12. Lovly CM, McDonald NT, Chen H, Ortiz-Cuaran S, Heukamp LC, Yan Y, Florin A, Ozretić L, Lim D, Wang L, Chen Z, Chen X, Lu P, Paik PK, Shen R, Jin H, Buettner R, Ansén S, Perner S, Brockmann M, Bos M, Wolf J, Gardizi M, Wright GM, Solomon B, Rusell PA, Rogers TM, Suehara Y, Red-Brewer M, Tieu R, de Stanchina E, Wang Q, Zhao Z, Johonson DH, Horn L, Wong KK, Thomas RK, Ladanyi M, Pao W (2014) Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med 20:1027–1034

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Xia J, Jia P, Hutchinson KE, Dahlman KB, Johnson D, Sosman J, Pao W, Zhao Z (2014) A meta-analysis of somatic mutations from next generation sequencing of 241 melanomas: a road map for the study of genes with potential clinical relevance. Mol Cancer Ther 13:1918–1928

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Jia P, Jin H, Meador CB, Xia J, Ohashi K, Liu L, Pirazzoli V, Dahmal KB, Politi K, Michor F, Zhao Z, Pao W (2013) Next-generation sequencing of paired tyrosine kinase inhibitor-sensitive and –resistant EGFR mutant lung cancer cell lines identifies spectrum of DNA changes associated with drug resistance. Genome Res 23:1434–1445

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Dahlman KB, Xia J, Hutchinson K, Ng C, Hucks D, Jia P, Atefi M, Su Z, Branch S, Lyle PL, Hicks DJ, Bozon V, Glaspy JA, Rosen N, Solit DB, Netterville JL, Vnencak-Jones c, Sosman JA, Ribas A, Zhao Z, Pao W (2012) BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov 2:791–797

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Cheng F, Zhao J, Zhao Z (2016) Advances in computational approaches for prioritizing driver mutations and significantly mutated genes in cancer genomes. Brief Bioinform 17:642–656

    Article  PubMed  CAS  Google Scholar 

  17. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Khan J, Ezan F, Crémet J, Fautrel A, Gilot D, Lambert M, Benaud C, Troadec MB, Prigent C (2011) Overexpression of active aurora-C kinase results in cell transformation and tumour formation. PLoS One 6:e26512

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Lim SK, Gopalan G (2007) Aurora-a kinase interacting protein 1 (AURKAIP1) promotes aurora-a degradation through an alternative ubiquitin-independent pathway. Biochem J 403:119–127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Fu J, Bian M, Jiang Q, Zhang C (2007) Roles of aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 5:1–10

    Article  PubMed  CAS  Google Scholar 

  21. Sun T, Miao X, Wang J, Tan W, Zhou Y, Yu C, Lin D (2004) Functional Phe31Ile polymorphism in aurora a and risk of breast carcinoma. Carcinogenesis 25:2225–2230

    Article  PubMed  CAS  Google Scholar 

  22. Xu J, Wu X, Zhou WH, Liu AW, Wu JB, Deng JY, Yue CF, Yang SB, Wang J, Yuan ZY, Liu Q (2013) Aurora-a identifies early recurrence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer. PLoS One 8:e56919

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Mendiola M, Barriuso J, Mariño-Enríquez A, Redondo A, Domínguez-Cáceres A, Hernández-Cortés G, Pérez-Fernández E, Sánchez-Navarro I, Vera JA, Suárez A, Espinosa E, González-Barón M, Palacios J, Hardisson D (2009) Aurora kinases as prognostic biomarkers in ovarian carcinoma. Hum Pathol 40:631–638

    Article  PubMed  CAS  Google Scholar 

  24. Dai ZJ, Kang HF, Wang XJ, Shao YP, Lin S, Zhao Y, Ren HT, Min WL, Wang M, Liu XX (2014) Association between genetic polymorphisms in AURKA (rs2273535 and rs1047972) and breast cancer risk: a meta-analysis involving 37,221 subjects. Cancer Cell Int 14:91

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. López-Cortés A, Echeverría C, Oña-Cisneros F, Sánchez ME, Herrera C, Cabrera-Andrade A, Rosales F, Ortiz M, Paz-y-Miño C (2015) Breast cancer risk associated with gene expression and genotype polymorphisms of thefolate-metabolizing MTHFR gene: a case-control study in a high altitude Ecuadorian mestizo population. Tumor Biol 36:6451–6461

    Article  CAS  Google Scholar 

  26. Rodriguez S, Gaunt TR, Day IN (2009) Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 169:505–514

    Article  PubMed  PubMed Central  Google Scholar 

  27. Engle LJ, Simpson CL, Landers JE (2006) Using high-throughput SNP technologies to study cancer. Oncogene 25:1594–1601

    Article  PubMed  CAS  Google Scholar 

  28. Fejerman L, Ahmadiyeh N, Hu D, Huntsman S, Beckman KB, Caswell JL, Tsung K, John EM, Torres-Mejia G, Carvajal-Carmona L, Echeverry MM, Tuazon AM, Ramirez C, COLUMBUS Consortium, Gognoux CR, Eng C, Gonzalez-Burchard E, Henderson B, Le Marchard L, Kooperberg C, Hou L, Agalliu I, Kraft P, Lindström S, Perez-Stable EJ, Haiman CA, Ziv E (2014) Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. Nat Commun 5:5260

    Article  PubMed  CAS  Google Scholar 

  29. Ruan Y, Song AP, Wang H, Xie YT, Han JY, Sajdik C, Tian XX, Fang WG (2011) Genetic polymorphisms in AURKA and BRCA1 are associated with breast cancer susceptibility in a Chinese Han population. J Pathol 225:535–543

    Article  PubMed  CAS  Google Scholar 

  30. Webb EL, Rudd MF, Houlston RS (2006) Case-control, kin-cohort and meta-analyses provide no support for STK15 F31I as a low penetrance colorectal cancer allele. Br J Cancer 95:1047–1049

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Miao X, Sun T, Wang Y, Zhang X, Tan W, Lin D (2004) Functional STK15 Phe31Ile polymorphism is associated with the occurrence and advanced disease status of esophageal squamous cell carcinoma. Cancer Res 64:2680–2683

    Article  PubMed  CAS  Google Scholar 

  32. Tang W, Qiu H, Ding H, Sun B, Wang L, Yin J, Gu H (2013) Association between the STK15 F31I polymorphism and cancer susceptibility: a meta-analysis involving 43,626 subjects. PLoS One 8:e82790

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Sun T, Miao X, Wang J, Tan W, Zhou Y, Yu C, Lin D (2004) Functional Phe31Ile polymorphism in aurora a and risk of breast carcinoma. Carcinogenesis 25:2225–2230

    Article  PubMed  CAS  Google Scholar 

  34. Dai Q, Cai QY, Shu XO, Ewart-Toland A, Wen WQ, Balmain A, Gao YT, Zheng W (2004) Synergistic effects of STK15 gene polymorphisms and endogenous estrogen exposure in the risk of breast cancer. Cancer Epidemiol Biomark Prev 13:2065–2070

    CAS  Google Scholar 

  35. Lo YL, Yu JC, Chen ST, Yang HC, Fann CS, Mau YC, Shen CY (2005) Breast cancer risk associated with genotypic polymorphism of the mitosis-regulating gene aurora-STK15/BTAK. Int J Cancer 115:276–283

    Article  PubMed  CAS  Google Scholar 

  36. MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk (2010) Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women. Breast Cancer Res Treat 120:727–736

    Article  CAS  Google Scholar 

  37. Tchatchou S, Wirtenberger M, Hemminki K, Sutter C, Meindl A, Wappenschmidt B, Kiechle M, Bugert P, Schmutzler RK, Bartram CR, Burweinkel B (2007) Aurora kinases a and B and familial breast cancer risk. Cancer Lett 247:266–272

    Article  PubMed  CAS  Google Scholar 

  38. Vidarsdottir L, Bodvarsdottir SK, Hilmarsdottir H, Tryggvadottir L, Eyfjord JE (2007) Breast cancer risk associated with AURKA 91T -->a polymorphism in relation to BRCA mutations. Cancer Lett 250:206–212

    Article  PubMed  CAS  Google Scholar 

  39. Fletcher O, Johnson N, Palles C, dos Santos Silva I, McCormack V, Whittaker J, Ashworth A, Peto J (2006) Inconsistent association between the STK15 F31I genetic polymorphism and breast cancer risk. J Natl Cancer Inst 98:1014–1018

    Article  PubMed  CAS  Google Scholar 

  40. Cox DG, Hankinson SE, Hunter DJ (2006) Polymorphisms of the AURKA (STK15/aurora kinase) gene and breast cancer risk (United States). Cancer Causes Control 17:81–83

    Article  PubMed  Google Scholar 

  41. Egan KM, Newcomb PA, Ambrosone CB, Trentham-Dietz A, Titus-Ernstoff L, Hampton JM, Kimura MT, Nagase H (2004) STK15 polymorphism and breast cancer risk in a population-based study. Carcinogenesis 25:2149–2153

    Article  PubMed  CAS  Google Scholar 

  42. Royce ME, Xia W, Sahin AA, Katayama H, Johnston DA, Hortobagyi G, Hung MC (2004) STK15/ aurora-a expression in primary breast tumors is correlated with nuclear grade but not with prognosis. Cancer 100:12–19

    Article  PubMed  CAS  Google Scholar 

  43. Loman N, Johannson O, Kristoffersson U, Olsson H, Borg A (2001) Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst 93:1215–1223

    Article  PubMed  CAS  Google Scholar 

  44. Lindström L, Karlsson E, Wilking UM, Johansson U, Hartman J, Lidbrink EK, Hatschek T, Skoog L, Bergh J (2012) Clinically used breast cancer markers such as estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol 30:2601–2608

    Article  PubMed  Google Scholar 

  45. Colditz G, Rosner BA, Chen WY, Holmes MD, Hankinson SE (2004) Risk factors for breast cancer according to estrogen and progesterone receptor status. J Natl Cancer Inst 96:218–228

    Article  PubMed  CAS  Google Scholar 

  46. López-Cortés A, Jaramillo-Koupermann G, Muñoz MJ, Cabrera A, Echeverría C, Rosales F, Vivar N, Paz-y-Miño C (2013) Genetic polymorphisms in MTHFR (C677T, A1298C), MTR (A2756G) and MTRR (A66G) genes associated with pathological characteristics of prostate cancer in the Ecuadorian population. Am J Med Sci 346:447–454

    Article  PubMed  Google Scholar 

  47. Paz-y-Miño C, Robles P, Salazar C, Leone PE, García Cárdenas JM, Naranjo M, López-Cortés A (2016) Positive association of the androgen receptor CAG repeat length polymorphism with the risk of prostate cancer. Mol Med Rep 14:1791–1798

    Article  PubMed  CAS  Google Scholar 

  48. Paz-y-Miño C, López-Cortés A, Muñoz MJ, Cabrera A, Castro B, Sánchez ME (2010) Incidence of the L858R and G719S mutations of the epidermal growth factor receptor oncogene in an Ecuadorian population with lung cancer. Cancer Genet Cytogenet 196:201–203

    Article  PubMed  CAS  Google Scholar 

  49. Paz-y-Miño C, Muñoz MJ, López-Cortés A, Cabrera A, Palacios A, Castro B, Paz-y-Miño N, Sánchez ME (2010) Frequency of polymorphisms pro198leu in GPX-1 gene and ile58thr in MnSOD gene in the altitude Ecuadorian population with bladder cancer. Oncol Res 18:395–400

    Article  PubMed  CAS  Google Scholar 

  50. Paz-y-Miño C, López-Cortés A, Muñoz MJ, Castro B, Cabrera A, Sánchez ME (2010) Relationship of an hRAD54 gene polymorphism (2290 C/T) in an Ecuadorian population with chronic myelogenous leukemia. Genet Mol Biol 33:646–649

    Article  PubMed  PubMed Central  Google Scholar 

  51. Quiñones LA, Lavanderos MA, Cayun JP, Garcia-Martin E, Agundez JA, Caceres DD, Roco AM, Morales JE, Herrera L, Encina G, Isaza CA, Redal MA, Larovere L, Soria NW, Eslava-Schmalbach J, Castaneda-Hernandez G, López-Cortés A, Magno LA, Lopez M, Chiurillo MA, Rodeiro I, Castro de Guerra D, Teran E, Estevez-Carrizo F, Lares Assef I (2014) Perception of the usefulness of drug/gene pairs and barriers for pharmacogenomics in Latin America. Curr Drug Metab 15:202–208

    Article  PubMed  CAS  Google Scholar 

  52. López-Cortés A, Guerrero S, Redal M, Alvarado A, Quiñones L (2017) State of Art of Cancer Pharmacogenomics in Latin American Populations. Int J Mol Sci 18(6):639

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Andrés López-Cortés or César Paz-y-Miño.

Ethics declarations

Conflict of Interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

López-Cortés, A., Cabrera-Andrade, A., Oña-Cisneros, F. et al. Breast Cancer Risk Associated with Genotype Polymorphisms of the Aurora Kinase a Gene (AURKA): a Case-Control Study in a High Altitude Ecuadorian Mestizo Population. Pathol. Oncol. Res. 24, 457–465 (2018). https://doi.org/10.1007/s12253-017-0267-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-017-0267-6

Keywords

Navigation