Polymorphic GT Dinucleotide Repeat in the PIK3CA Gene and its Association with Colorectal Cancer Risk

Document Type : Original Article (s)

Authors

1 MSc Student, Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran

2 Associate Professor, Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran

3 Assistant Professor, Department of Radiotherapy, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: The PIK3CA oncogene, which encodes p110α, is one of the most mutated genes in human cancers such as colorectal. A polymorphic GT dinucleotide repeat exists in intron 1 of the PIK3CA gene. Till this research, there were no study on polymorphism of PIK3CA gene microsatellites and their relationship with cancer risk. In the present study, we investigated GT repeat polymorphism in the intron 1 of this gene among patients with colorectal cancer and healthy individuals and evaluated the association between this polymorphism and the potential genetic susceptibility to the development of colorectal cancer.Methods: Peripheral blood samples were collected from 103 patients with colorectal cancer and 100 healthy blood donors. After DNA extraction, GT dinucleotide region was amplified using polymerase chain reaction (PCR) technique and the number of GT repeats was determined via polyacrylamide gel electrophoresis.Findings: Eight distinct alleles were identified in these subjects, ranging in size from 13 to 20 GT repeats. People with two alleles shorter than 17 GT repeat had a significantly higher risk of developing colorectal cancer (OR = 3.65, P = 9 × 10-6); in contrast, people with two alleles longer than 16 GT repeat were at a significantly lower risk of colorectal cancer (OR = 0.18, P = 3.5 × 10-6).Conclusion: Our findings indicate significant relationship between the numbers of repetitive sequences in intron 1 of PIK3CA gene and the risk of colorectal cancer.

Keywords

References

  1. Alison MR, Lim SM, Nicholson LJ. Cancer stem cells: problems for therapy? J Pathol 2011; 223(2): 148-62.
  2. Martinez JD, Parker MT, Fultz KE, Ignatenko NA, Gerner EW. Molecular biology of cancer. Burger's medicinal chemistry and drug discovery. New York, NY: John Wiley and Sons, Inc.; 2003. p. 213-21.
  3. Aune D, Chan DS, Lau R, Vieira R, Greenwood DC, Kampman E, et al. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. BMJ 2011; 343: d6617.
  4. Liu KQ, Liu ZP, Hao JK, Chen L, Zhao XM. Identifying dysregulated pathways in cancers from pathway interaction networks. BMC Bioinformatics 2012; 13: 126.
  5. Ikenoue T, Kanai F, Hikiba Y, Obata T, Tanaka Y, Imamura J, et al. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 2005; 65(11): 4562-7.
  6. Karakas B, Bachman KE, Park BH. Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 2006; 94(4): 455-9.
  7. Guo XN, Rajput A, Rose R, Hauser J, Beko A, Kuropatwinski K, et al. Mutant PIK3CA-bearing colon cancer cells display increased metastasis in an orthotopic model. Cancer Res 2007; 67(12): 5851-8.
  8. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004; 304(5670): 554.
  9. Barault L, Veyrie N, Jooste V, Lecorre D, Chapusot C, Ferraz JM, et al. Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int J Cancer 2008; 122(10): 2255-9.
  10. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16(3): 1215.
  11. Sawaya S, Bagshaw A, Buschiazzo E, Kumar P, Chowdhury S, Black MA, et al. Microsatellite tandem repeats are abundant in human promoters and are associated with regulatory elements. PLoS One 2013; 8(2): e54710.
  12. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med 2009; 361(25): 2449-60.
  13. Weber JL, Wong C. Mutation of human short tandem repeats. Hum Mol Genet 1993; 2(8): 1123-8.
  14. Hui J, Hung LH, Heiner M, Schreiner S, Neumuller N, Reither G, et al. Intronic CA-repeat and CA-rich elements: a new class of regulators of mammalian alternative splicing. EMBO J 2005; 24(11): 1988-98.
  15. Zhang W, He L, Liu W, Sun C, Ratain MJ. Exploring the relationship between polymorphic (TG/CA)n repeats in intron 1 regions and gene expression. Hum Genomics 2009; 3(3): 236-45.
  16. Levinson G, Gutman GA. High frequencies of short frameshifts in poly-CA/TG tandem repeats borne by bacteriophage M13 in Escherichia coli K-12. Nucleic Acids Res 1987; 15(13): 5323-38.
  17. Cathomas G. PIK3CA in Colorectal Cancer. Front Oncol 2014; 4: 35.
  18. Sharma VK, Kumar N, Brahmachari SK, Ramachandran S. Abundance of dinucleotide repeats and gene expression are inversely correlated: a role for gene function in addition to intron length. Physiol Genomics 2007; 31(1): 96-103.
  19. Agarwal AK, Giacchetti G, Lavery G, Nikkila H, Palermo M, Ricketts M, et al. CA-Repeat polymorphism in intron 1 of HSD11B2: effects on gene expression and salt sensitivity. Hypertension 2000; 36(2): 187-94.
  20. Dufour C, Capasso M, Svahn J, Marrone A, Haupt R, Bacigalupo A, et al. Homozygosis for (12) CA repeats in the first intron of the human IFN-gamma gene is significantly associated with the risk of aplastic anaemia in Caucasian population. Br J Haematol 2004; 126(5): 682-5.
  21. Zhang W, He L, Liu W, Sun C, Ratain MJ. Exploring the relationship between polymorphic (TG/CA)n repeats in intron 1 regions and gene expression. Hum Genomics 2009; 3(3): 236-45.
  22. Gemayel R, Cho J, Boeynaems S, Verstrepen KJ. Beyond junk-variable tandem repeats as facilitators of rapid evolution of regulatory and coding sequences. Genes (Basel ) 2012; 3(3): 461-80.
  23. Gao PS, Heller NM, Walker W, Chen CH, Moller M, Plunkett B, et al. Variation in dinucleotide (GT) repeat sequence in the first exon of the STAT6 gene is associated with atopic asthma and differentially regulates the promoter activity in vitro. J Med Genet 2004; 41(7): 535-9.
  24. Shimajiri S, Arima N, Tanimoto A, Murata Y, Hamada T, Wang KY, et al. Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Lett 1999; 455(1-2): 70-4.
  25. Phipps AI, Makar KW, Newcomb PA. Descriptive profile of PIK3CA-mutated colorectal cancer in postmenopausal women. Int J Colorectal Dis 2013; 28(12): 1637-42.
  26. Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 2009; 69(5): 1851-7.
  27. Kato S, Iida S, Higuchi T, Ishikawa T, Takagi Y, Yasuno M, et al. PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. Int J Cancer 2007; 121(8): 1771-8.
  28. Gebhardt F, Zanker KS, Brandt B. Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem 1999; 274(19): 13176-80.
  29. Rosty C, Young JP, Walsh MD, Clendenning M, Sanderson K, Walters RJ, et al. PIK3CA activating mutation in colorectal carcinoma: associations with molecular features and survival. PLoS One 2013; 8(6): e65479.
  30. Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012; 367(17): 1596-606.
Journal of Isfahan Medical School
Volume 33, Issue 330 - Serial Number 330
March and April 2015
Pages 484-494

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History

  • Receive Date: 20 June 2014
  • Revise Date: 01 November 2024
  • Accept Date: 06 April 2022

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