Positive Association between the Polymorphic Variant CCND1 A870G and Colorectal Cancer in Ecuadorian Mestizo Population

• César Paz-y-Miño

  Instituto de Investigaciones Biomédicas, Facultad de Ciencias de la Salud, Universidad de las Américas, Quito, Ecuador

• Carolina Salazar

  Instituto de Investigaciones Biomédicas, Facultad de Ciencias de la Salud, Universidad de las Américas, Quito, Ecuador

• Tania Zurita

  Instituto de Investigaciones Biomédicas, Facultad de Ciencias de la Salud, Universidad de las Américas, Quito, Ecuador

• Andrés López-Cortés

  Instituto de Investigaciones Biomédicas, Facultad de Ciencias de la Salud, Universidad de las Américas, Quito, Ecuador

• Ramiro Hidalgo

  Department of Pathology, Solon Espinosa Ayala Oncological Hospital, Quito, Ecuador

• Felipe Rosales

  Department of Pathology, Solon Espinosa Ayala Oncological Hospital, Quito, Ecuador

• Alexandra Montalvo

  Department of Pathology, Pablo Arturo Suárez Hospital, Quito, Ecuador

• Paola E. Leone

  Instituto de Investigaciones Biomédicas, Facultad de Ciencias de la Salud, Universidad de las Américas, Quito, Ecuador

Background: Colorectal cancer (CRC) is the fourth most common cause of cancer death worldwide and has an annual incidence of 917,000 cases. In Ecuador the CRC is the fifteenth most common form of cancer and the fourth leading cause of cancer deaths. Aim: Our goal was to establish frequencies related to the polymorphic variants: (CA)n in the EGFR gene and A870G in the CCND1 gene and their influence on the development of CRC in the Ecuadorian population. Methods: This is a retrospective case-control study consisting of colorectal cancer patients (n = 96 cancer tissues) compared to a control group (n = 62 adjacent healthy tissues). For the sequencing of the fragments, PCR and Sanger method was used. Results: The polymorphic variant A870G in CCND1 has a genotype frequency for the common homozygous G/G = 0.69, for the heterozygous A/G = 0.25 and for the less frequent homozygous A/A = 0.06 in the control group. We studied 7 alleles, repeats 14-19 have been reported in other studies, but the 13 repeats allele was first described here. The most common number of repetitions was 18 with a frequency of 0.326 in patients and 0.25 in controls (2 = 22.58, p <0.01). The odds ratio showed that the risk of developing colorectal cancer is 5 times greater if the individual is carrying the heterozygous G/A (p <0.01). Meanwhile, if the individual is carrying the allele 'A' the risk is 4 times more likely to develop this disease (p <0.01).

WH Organization. (2014, 25 June). GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. 2012. Available: http://globocan.iarc.fr/ Default.aspx

CR. UK. (2014, 24 June). Worldwide cancer statistics. In: Cancer statistics. Available: www.cancerresearchuk.org/ cancer-info/cancerstats/world

Meyerhardt J, Skarin AT, Saunders M. Colorectal Cancer, 2001.

Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012; 486: 532-6. http://dx.doi.org/10.1038/nature11156

Le Marchand L, Seifried A, Lum-Jones A, Donlon T, Wilkens LR. Association of the cyclin D1 A870G polymorphism with advanced colorectal cancer. JAMA 2003; 290: 2843-8. http://dx.doi.org/10.1001/jama.290.21.2843

S. d. L. C. e. Cáncer, Cancer epidemiology. National Tumor Registry: Quito: RNT, 2005.

Caserras XB, Martínez RJ. Cancer: Elsevier, 2010.

S. E. d. O. Médica. Cáncer de colon y recto 2013. Available: http://www.seom.org/en/informacion-sobre-el-cancer/info-tipos-cancer/digestivo/colon-recto?start=2

Porter TR, Richards FM, Houlston RS, Evans DG, Jankowski JA, Macdonald F, et al. Contribution of cyclin d1 (CCND1) and E-cadherin (CDH1) polymorphisms to familial and sporadic colorectal cancer. Oncogene 2002; 21: 1928-33. http://dx.doi.org/10.1038/sj.onc.1205245

KRAS Testing for Anti-EGFR Therapy in Advanced Colorectal Cancer: An Evidence-Based and Economic Analysis. Ont Health Technol Assess Ser 2010; 10: 1-49.

Lai C, Sung FC, Hseih L-L, Tang R, Chiou H-Y, Wu F-Y, et al. Associations between genetic polymorphisms of epidermal growth factor receptor (EGFR) and survival of colorectal cancer (CRC) patients treated with 5-fluorouracil-based chemotherapy. Annals of Surgical Oncology 2013; 20: 7. http://dx.doi.org/10.1245/s10434-013-3069-4

Fakih M. Biologic therapies in colorectal cancer: indications and contraindications. Am Soc Clin Oncol Educ Book 2015; 35: e197-206. http://dx.doi.org/10.14694/EdBook_AM.2015.35.e197

Hezel AF, Deshpande V, Zhu AX. Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol 2010; 28: 3531-40. http://dx.doi.org/10.1200/JCO.2009.27.4787

Nie F, Shen J, Tong JL, Xu XT, Zhu MM, Ran ZH. Meta-analysis: the efficacy and safety of monoclonal antibody targeted to epidermal growth factor receptor in the treatment of patients with metastatic colorectal cancer. J Dig Dis 2009; 10: 247-57. http://dx.doi.org/10.1111/j.1751-2980.2009.00393.x

Hanawa M, Suzuki S, Dobashi Y, Yamane T, Kono K, Enomoto N, et al. EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus. Int J Cancer 2006; 118: 1173-80. http://dx.doi.org/10.1002/ijc.21454

Liu W, Innocenti F, Chen P, Das S, Cook EH, Jr., Ratain MJ. Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism. Clin Cancer Res 2003; 9: 1009-12.

Amador M. An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Research 2004; p. 8. http://dx.doi.org/10.1158/0008-5472.can-04-1036

Inoue M, Takahashi S, Soeda H, Shimodaira H, Watanabe M, Miura K, et al. Gene-expression profiles correlate with the efficacy of anti-EGFR therapy and chemotherapy for colorectal cancer. Int J Clin Oncol 2015. http://dx.doi.org/10.1007/s10147-015-0841-4

Moreno-Bueno G, Rodriguez-Perales S, Sanchez-Estevez C, Hardisson D, Sarrio D, Prat J. et al. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 2003; 22: 6115-8. http://dx.doi.org/10.1038/sj.onc.1206868

Huang CY, Tsai CW, Hsu CM, Chang WS, Shui HA, Bau DT. The significant association of CCND1 genotypes with colorectal cancer in Taiwan. Tumour Biol 2015. http://dx.doi.org/10.1007/s13277-015-3347-9

Sameer AS, Parray FQ, Dar MA, Nissar S, Banday MZ, Rasool S, et al. Cyclin D1 G870A polymorphism and risk of colorectal cancer: a case control study. Mol Med Rep 2013; 7: 811-5.

Schernhammer E. Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma. British Journal of Cancer 2006; p. 6. http://dx.doi.org/10.1038/sj.bjc.6603007

Yang Y, Wang F, Shi C, Zou Y, Qin H, Ma Y. Cyclin D1 G870A polymorphism contributes to colorectal cancer susceptibility: evidence from a systematic review of 22 case-control studies. PLoS One 2012; 7: e36813.

Al-Qasem A, Al-Howail HA, Al-Swailem M, Al-Mazrou A, Al-Otaibi B, Al-Jammaz I, et al. PAC exhibits potent anti-colon cancer properties through targeting cyclin D1 and suppressing epithelial-to-mesenchymal transition. Mol Carcinog 2015.

Jiang J, Wang J, Suzuki S, Gajalakshmi V, Kuriki K, Zhao Y, et al. Elevated risk of colorectal cancer associated with the AA genotype of the cyclin D1 A870G polymorphism in an Indian population. J Cancer Res Clin Oncol 2006; 132: 193-9. http://dx.doi.org/10.1007/s00432-005-0039-7

A. S. o. C. Oncology. Cancer 2013; 2014.

WH Organization. medical factsheets 2014. Available: http://www.who.int/mediacentre/factsheets/fs297/es/

Srinivasan M, Sedmak D, Jewell S. Effect of Fixatives and Tissue Processing on the Content and Integrity of Nucleic Acids. The American Journal of Pathology 2002; 161: 1961-1971.

Nam SK, Im J, Kwak Y, Han N, Nam KH, Seo AN, et al. Effects of Fixation and Storage of Human Tissue Samples on Nucleic Acid Preservation. Korean Journal of Pathology 2014; 48: 36-42.

Bustamante J, Astudillo M, Pazos M, Bravo L. Evaluation of Two Methods DNA Extraction from Formalin-Fixed Paraffin-Embedded Tissues on Non-Optimal Conditions. Acta Biologica Colombiana 2011; 16: 15.

Weihua Z, Tsan R, Huang W, Wu Q, Chiu C, Isaiah J, et al. Survival of Cancer Cells Is Maintained by EGFR Independent of Its Kinase Activity. Cancer Cell 2008; 13: 8. http://dx.doi.org/10.1016/j.ccr.2008.03.015

Pabalan N, Bapat B, Sung L, Jarjanazi H, Francisco-Pabalan O, Ozcelik H. Cyclin D1 Pro241Pro (CCND1-G870A) Polymorphism Is Associated with Increased Cancer Risk in Human Populations: A Meta-Analysis. Cancer Epidemiology Biomarkers & Prevention 2008; 17: 2773-2781.

López A, Muñoz M, Paz-y-Miño C. Genetic polymorphisms and their association with altered proteins in Ecuadorian individuals with cancer. Ecuadorian Journal of Medicine and Biological Sciences 2011; p. 14.

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