Association of rs712 polymorphism in a let-7 microRNA-binding site of KRAS gene with colorectal cancer in a Mexican population

Document Type: Original Article


1 División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, México

2 Medicina Molecular, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Mexico

3 Laboratorio de Inmunofarmacología, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

4 Servicio de Oncología, Unidad Médica de Alta Especialidad, Hospital de Especialidades, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco, Mexico


Objective(s): The rs712 polymorphism in a let-7 microRNA-binding site at KRAS gene has been associated with cancer. To examine its association with rs712 polymorphism, we analyzed Mexican individuals with colorectal cancer (CRC) and healthy subjects.
Materials and Methods: Genotyping of the rs712 polymorphism was performed by polymerase chain reaction in 281 controls and 336 CRC patients.
Results: The observed frequencies of rs712 polymorphism indicated an associated protective factor for CRC (P=0.032). An association between genotype and the disease was evident in: colon localization (allele T, odds ratio (OR) 3.82, 95% confidence Intervals (CI) 2.77-5.28, P=0.0001), node metastasis (genotype TT, OR 2.49, 95% CI 1.45-4.28, P=0.0009), poor differentiation (genotype GT, OR 2.35, 95% CI 1.35-4.1, P=0.0033), and poor chemotherapy response (genotype GT, OR 2.6, 95% CI 1.7-4.24, P=0.0001).
Conclusion: Comparison of the data from patients with control group showed that polymorphism of rs712 in KRAS gene was protective factor, which was associated with susceptibility for CRC. However, the genotypes TT and GT of rs712 polymorphism in KRAS could contribute significantly to colon localization, node metastasis, poor differentiation and poor chemotherapy response in CRC patients in this sample population.


Main Subjects

1. Alberts SR, Citrin D, Schwartz D, Rodriguez M. Colon, Rectal, and Anal Cancers. Cancer Management. 2016;
2. Pourhoseingholi MA. Epidemiology and burden of colorectal cancer in asia-pacific region: what shall we do now?. Transl Gastrointest Cancer 2014; 3:169-173.
3. Gutiérrez IA, Puebla AM, Delgado JI, Figuera LE, Zúñiga GM, Gómez K, et al. Association between TNF-α-308G>A and -238G>A gene polymorphisms and TNF-α serum levels in mexican colorectal cancer patients. Genet Mol Res 2016; 15:1-11.
4. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin 2014; 64:104-117.
5. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in globocan 2012. Int J Cancer 2015; 136:359-386.
6. García S, Téllez FI, Méndez N, Uribe M. Results of the first program of colorectal cancer screening in mexico. Endoscopia 2015; 27:59-63.
7. OMIM entry 190070. V-KI-RAS2 Kirsten rat sarcoma viral
oncogene homolog; KRAS.
8. Jancík S, Drábek J, Radzioch D, Hajdúch M. Clinical relevance of KRAS in human cancers. J Biomed Biotechnol 2010; 2010:150960-150973.
9. Liu X, Jakubowski M, Hunt JL. KRAS gene mutation in colorectal cancer is correlated with increased proliferation and spontaneous apoptosis. Am J Clin Pathol 2011; 135: 245-252.
10. Jiang QH, Peng HX, Zhang Y, Tian P, Xi ZL, Chen H. rs712 polymorphism within let-7 microRNA-binding site might be involved in the initiation and progression of colorectal cancer in chinese population. Onco Targets Ther 2015; 8:3041-3045.
11. Du XY, Hu YY, Xie C, Deng CY, Liu CY, Luo ZG, et al. Significant association between Let-7-KRAS rs712 G > T polymorphism and cancer risk in the chinese population: a meta-analysis. Oncotarget 2017; 8:13863-13871.
12. Chan SH, Wang LH. Regulation of cancer metastasis by microRNAs. J Biomed Sci 2015; 22:9-21.
13. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16:1215-1216.
14. Li ZH, Pan XM, Han BW, Guo XM, Zhang Z, Jia J, et al. A let-7 binding site polymorphism rs712 in the KRAS 3’ UTR is associated with an increased risk of gastric cancer. Tumour Biol 2013; 34:3159-3163.
15. Sanguinetti CJ, Dias E, Simpson AJ. Rapid silver staining and recovery of PCR products separated on polyacrylamide gels. Biotechniques 1994; 17:914-921.
16. Zhang W, Winder T, Ning Y, Pohl A, Yang D, Kahn M, et al. A let-7 microRNA-binding site polymorphism in 3’-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy. Ann Oncol 2011; 22:104-109.
17. Schulte PA, Whittaker C, Curran CP. Considerations for using genetic and epigenetic information in occupational health risk assessment and standard setting. J Occup Environ Hyg 2015; 12:69-81.
18. Sanaei S, Hashemi M, Eskandari E, Hashemi SM, Bahari G. KRAS gene polymorphisms and their impact on breast cancer risk in an iranian population. Asian Pac J Cancer Prev 2017; 18:1301-1305.
19. Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, et al. Let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131:1109-1123.
20. Cong T, Xiang D. KRAS mutation testing in metastatic colorectal cancer. World J Gastroenterol 2012; 18:5171-5180.
21. Deschoolmeester V, Baay M, Specenier P, Lardon F, Vermorken JB. A review of the most promising biomarkers in colorectal cancer: one step closer to targeted therapy. Oncologist 2010; 15:699-731.
22. Akao Y, Nakagawa Y, Naoe T. let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol Pharm Bull 2006; 29:903-906.
23. Dong Y, Yu J, Ng SS. MicroRNA dysregulation as a prognostic biomarker in colorectal cancer. Cancer Manag Res 2014; 6:405-422.
24. Singh R, Mo YY. Role of microRNAs in breast cancer. Cancer Biol Ther 2013; 14:201-212.
25. Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol 1988; 6:1653-1664.
26. Ryan R, Gibbons D, Hyland JM, Treanor D, White A, Mulcahy HE, et al. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology 2005; 47:141-146.