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Lack of mutational events of RAS genes in sporadic thyroid cancer but high risk associated with HRAS T81C single nucleotide polymorphism (case–control study)

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Tumor Biology

Abstract

High incidence of thyroid cancer worldwide indicates the importance of studying genetic alterations that lead to its carcinogenesis. Specific acquired RAS mutations have been found to predominate in different cancers, and HRAS T81C polymorphism has been determined to contribute the risk of various cancers, including thyroid cancer. We screened the exons 1 and 2 of RAS genes (HRAS, KRAS, and NRAS) in 60 consecutive thyroid tissue (tumor and adjacent normal) samples, and a case–control study was also conducted for HRAS T81C polymorphism in HRAS codon 27 using the polymerase chain reaction-restriction fragment length polymorphism to test the genotype distribution of 140 thyroid cancer patients in comparison with 170 cancer-free controls from a Kashmiri population. No mutation was found in any of the thyroid tumor tissue samples, but we frequently detected polymorphism at nucleotide 81 (T > C) in exon 1 of HRAS gene. In HRAS T81C SNP, frequencies of TT, TC, and CC genotypes among cases were 41.4, 38.6, and 20.0 %, while in controls genotype frequencies were 84.1, 11.7, and 4.2 %, respectively. A significant difference was observed in variant allele frequencies (TC + CC) between the cases and controls (58.6 vs. 16 %) with odds ratio = 7.4; confidence interval (CI) = 4.3–12.7 (P < 0.05). Interestingly, combined TC and CC genotype abundantly presented in follicular thyroid tumor (P < 0.05). Moreover, a significant association of the variant allele (TC + CC) was found with nonsmokers (P < 0.05). This study shows that although thyroid cancer is highly prevalent in this region, the mutational events for RAS genes do not seem to be involved. Contrary to this HRAS T81C SNP of HRAS gene moderately increases thyroid cancer risk with rare allele as a predictive marker for follicular tumors.

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References

  1. Holt EH. Care of the pregnant thyroid cancer patient. Curr Opin Oncol. 2010;22:1–5.

    Article  PubMed  Google Scholar 

  2. Jemal A, Siegel R, Ward E, Hao Y, et al. Cancer statistics. CA Cancer J Clin. 2010;59:225–49.

    Article  Google Scholar 

  3. John D, Cramer BS, Pingfu F, et al. Analysis of the rising incidence of thyroid cancer using the Surveillance, Epidemiology and End Results national cancer data registry. Surgery. 2010;148:1147–53.

    Article  Google Scholar 

  4. Kondo T, Ezzat S, Sylvia L. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6:292–306.

    Article  PubMed  CAS  Google Scholar 

  5. Mazzaferri EL, Massoll N. Management of papillary and follicular (differentiated) thyroid cancer: new paradigms using recombinant human thyrotropin. Endocr Relat Cancer. 2002;9:227–47.

    Article  PubMed  CAS  Google Scholar 

  6. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med. 1998;338:297–306.

    Article  PubMed  CAS  Google Scholar 

  7. Adeniran AJ, Zhu Z, Gandhi M, et al. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol. 2006;30:216–22.

    Article  PubMed  Google Scholar 

  8. Kimura ET, Nikiforova MN, Zhu Z, et al. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res. 2003;63:1454–7.

    PubMed  CAS  Google Scholar 

  9. Soares P, Trovisco V, Rocha AS, et al. BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 2003;22:4578–80.

    Article  PubMed  CAS  Google Scholar 

  10. Frattini M, Ferrario C, Bressan P, et al. Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene. 2004;23:7436–40.

    Article  PubMed  CAS  Google Scholar 

  11. Rapa I, Saggiorato E, Giachino D, et al. Mammalian target of rapamycin pathway activation is associated to RET mutation status in medullary thyroid carcinoma. J Clin Endocrinol Metab. 2011;96:2146–53.

    Article  PubMed  CAS  Google Scholar 

  12. Basolo F, Pisaturo F, Pollina LE, Fontanini G, Elisei R, Molinaro E, Iacconi P, Miccoli P, Pacini F. N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. Thyroid. 2000;10:19–23.

    Article  PubMed  CAS  Google Scholar 

  13. Yoshimoto K, Iwahana H, Fukuda A, Sano T, Katsuragi K, Kinoshita M, Saito S, Itakura M. Ras mutations in endocrine tumors: mutation detection by polymerase chain reaction-single strand conformation polymorphism. Jpn J Cancer Res. 1992;83:1057–62.

    Article  PubMed  CAS  Google Scholar 

  14. Dockhorn-Dworniczak B, Caspari S, Schroder S, Bocker W, Dworniczak B. Demonstration of activated oncogenes of the ras family in human thyroid tumors using the polymerase chain reaction. Verh Dtsch Gas Pathol. 1990;74:415–8.

    CAS  Google Scholar 

  15. Schulten HJ, Al-Maghrabi J, Al-Ghamdi K, Salama S, Al-Muhayawi S, Chaudhary A, Hamour O, Abuzenadah A, Gari M, Al-Qahtani M. Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, AKT1, and CTNNB1 in medullary thyroid carcinoma. Anticancer Res. 2011;31:4179–83.

    PubMed  CAS  Google Scholar 

  16. Ciampi R, Mian C, et al. Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series. Thyroid. 2012. doi:10.1089/thy.2012-0207.

  17. Moura MM, Cavaco BM, Pinto E, Leite V. High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. Endocr Res. 2011. doi:10.1210/jc.2010-1921.

  18. Nikiforov YE. Molecular analysis of thyroid tumors. Mod Pathol. 2011;24:34–43.

    Article  Google Scholar 

  19. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–9.

    PubMed  CAS  Google Scholar 

  20. Fujita J, Yoshida O, Yuasa Y, et al. Ha-ras oncogenes are activated by somatic alterations in human urinary tract tumours. Nature. 1984;309:464–6.

    Article  PubMed  CAS  Google Scholar 

  21. Bos JL. The ras gene family and human carcinogenesis. Mutat Res. 1988;195:255–71.

    Article  PubMed  CAS  Google Scholar 

  22. Hashimoto-Gotoh T, Kikuno R, Takahashi M, et al. Possible role of the first intron of c-H-ras in gene expression: anti-cancer elements in oncogenes. Anticancer Res. 1988;8:851–9.

    PubMed  CAS  Google Scholar 

  23. Taparowsky E, Suard Y, Fasano O, et al. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature. 1982;300:762–5.

    Article  PubMed  CAS  Google Scholar 

  24. Esapa CT, Johnson SJ, Kendall-Taylor P, et al. Prevalence of Ras mutations in thyroid neoplasia. Clinical Endocrinol (Oxf). 1999;50:529–35.

    Article  CAS  Google Scholar 

  25. Capon DJ, Chen EY, Levinson AD, et al. Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature. 1983;302:33–7.

    Article  PubMed  CAS  Google Scholar 

  26. Kreimer-Erlacher H, Seidl H, Bäck B, et al. High mutation frequency at Ha-ras exons 1–4 in squamous cell carcinomas from PUVA-treated psoriasis patients. Photochem Photobiol. 2001;74:323–30.

    Article  PubMed  CAS  Google Scholar 

  27. Sathyan KM, Nalinakumari KR, Abraham T, et al. Influence of single nucleotide polymorphisms in H-Ras and cyclin D1 genes on oral cancer susceptibility. Oral Oncol. 2006;42:607–13.

    Article  PubMed  CAS  Google Scholar 

  28. Johne A, Roots I, Brockmoller J. A single nucleotide polymorphism in the human H-ras proto-oncogene determines the risk of urinary bladder cancer. Cancer Epidemiol Biomarkers Prev. 2003;12:68–70.

    PubMed  CAS  Google Scholar 

  29. Zhang Y, Jin M, Liu B, et al. Association between H-RAS T81C genetic polymorphism and gastrointestinal cancer risk: a population based case–control study in China. BMC Cancer. 2008;8:256–62.

    Article  PubMed  Google Scholar 

  30. Castro P, Soares P, Gusmão L, et al. H-RAS 81 polymorphism is significantly associated with aneuploidy in follicular tumors of the thyroid. Oncogene. 2006;25:4620–7.

    Article  PubMed  CAS  Google Scholar 

  31. Pandith AA, Shah ZA, Khan NP, et al. HRAS T81C polymorphism modulates risk of urinary bladder cancer and predicts advanced tumors in ethnic Kashmiri population. Urol Oncol. 2011. doi:10.1016/j.urolonc.2011.03.004.

  32. Adel H, Carolyn D, Darren C, et al. FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene. 2005;24:5218–25.

    Article  Google Scholar 

  33. Nakao M, Janssen J, Seriu T, et al. Rapid and reliable detection of N-ras mutations in acute lymphoblastic leukemia by melting curve analysis using Light Cycler technology. Leukemia. 2000;14:312–5.

    Article  PubMed  CAS  Google Scholar 

  34. Kumar R, Angelini S, Hemminki K. Activating BRAF and N-Ras mutations in sporadic primary melanomas: an inverse association with allelic loss on chromosome 9. Oncogene. 2003;22:9217–24.

    Article  PubMed  CAS  Google Scholar 

  35. Baea NC, Chaeb MH, Leec MH, et al. EGFR, ERBB2, and KRAS mutations in Korean non-small cell lung cancer patients. Cancer Genet Cytogenet. 2007;173:107–13.

    Article  Google Scholar 

  36. Bosari S, Marchetti A, Buttitta F, et al. Detection of p53 mutations by single strand conformation polymorphism (SSCP) gel electrophoresis: a comparative study of radioactive and non-radioactive silver-stained SSCP analysis. Diagn Mol Pathol. 1995;4:249–55.

    Article  PubMed  CAS  Google Scholar 

  37. Basolo F, Pisaturo F, Pollina LE, et al. N-ras mutation in poorly differentiated thyroid carcinomas: correlation with bone metastases and inverse correlation to thyroglobulin expression. Thyroid. 2000;10:19–23.

    Article  PubMed  CAS  Google Scholar 

  38. Lemoine NR, Mayall ES, Wyllie FS, et al. High frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene. 1989;4:159–64.

    PubMed  CAS  Google Scholar 

  39. Suarez HG, du Villard JA, Severino M, et al. Presence of mutations in all three ras genes in human thyroid tumors. Oncogene. 1990;5:565–70.

    PubMed  CAS  Google Scholar 

  40. Motoi N, Sakamoto A, Yamochi T, et al. Role of ras mutation in the progression of thyroid carcinoma of follicular epithelial origin. Pathol Res Pract. 2000;196:1–7.

    Article  PubMed  CAS  Google Scholar 

  41. Lemoine NR, Mayall ES, Wyllie FS, et al. Activated ras oncogenes in human thyroid cancers. Cancer Res. 1988;48:4459–63.

    PubMed  CAS  Google Scholar 

  42. Suarez HG, Du Villard JA, Caillou B, et al. Detection of activated ras oncogenes in human thyroid carcinomas. Oncogene. 1988;2:403–6.

    PubMed  CAS  Google Scholar 

  43. Wright PA, Lemoine NR, Mayall ES, et al. Papillary and follicular thyroid carcinomas show a different pattern of ras oncogene mutation. Br J Cancer. 1989;60:576–87.

    Article  PubMed  CAS  Google Scholar 

  44. Namba H, Rubin SA, Fagin JA. Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Mol Endocrinol. 1990;4:1474–9.

    Article  PubMed  CAS  Google Scholar 

  45. Fusco A, Berlingieri MT, Di Fiore PP, et al. One- and two-step transformations of rat thyroid epithelial cells by retroviral oncogenes. Mol Cell Biol. 1987;7:3365–70.

    PubMed  CAS  Google Scholar 

  46. Said S, Schlumberger M, Suarez HG. Oncogenes and anti-oncogenes in human epithelial thyroid tumors. J Endocrinol Investig. 1994;17:371–9.

    CAS  Google Scholar 

  47. Naito H, Pairojkul C, Kitahori Y, et al. Different ras gene mutational frequencies in thyroid papillary carcinomas in Japan and Thailand. Cancer Lett. 1998;131:171–5.

    Article  PubMed  CAS  Google Scholar 

  48. Karga H, Lee JK, Vickery AL, et al. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab. 1991;73:832–6.

    Article  PubMed  CAS  Google Scholar 

  49. Pilotti S, Collini P, Mariani L, et al. Insular carcinoma: a distinct de novo entity among follicular carcinomas of the thyroid gland. Am J Surg Pathol. 1997;21:1466–73.

    Article  PubMed  CAS  Google Scholar 

  50. Bouras M, Bertholon J, Dutrieux-Berger N, et al. Variability of Ha-ras (codon 12) proto-oncogene mutations in diverse thyroid cancers. Eur J Endocrinol. 1998;139:209–16.

    Article  PubMed  CAS  Google Scholar 

  51. Ivkovic TC, Loncar B, Spaventi R, et al. Association of H-ras polymorphisms and susceptibility to sporadic colon cancer. Int J Oncol. 2009;35:1169–73.

    CAS  Google Scholar 

  52. Lowy DR, Willumsen BM. Function and regulation of ras. Annu Rev Biochem. 1993;62:851–91.

    Article  PubMed  CAS  Google Scholar 

  53. Trepicchio WL, Krontiris TG. Members of the rel/NF-B family of transcriptional regulatory proteins bind the HRAS1 minisatellite DNA sequence. Nucleic Acids Res. 1992;20:2427–34.

    Article  PubMed  CAS  Google Scholar 

  54. Kotsinas A, Gorgoulis VG, Zacharatos P, et al. Additional characterization of a hexanucleotide polymorphic site in the first intron of human HRAS gene: comparative study of its alterations in non-small cell lung carcinomas and sporadic invasive breast carcinomas. Cancer Genet Cytogenet. 2001;126:147–54.

    Article  PubMed  CAS  Google Scholar 

  55. Fisher C, Mannino DM, Herman WH, et al. Cigarette smoking and thyroid hormone levels in males. Int J Epidemiol. 1997;26:972–7.

    Article  PubMed  CAS  Google Scholar 

  56. Ericsson UB, Lindgrade F. Effects of cigarette smoking on thyroid function and the prevalence of goitre, thyrotoxicosis and autoimmune thyroiditis. J Int Med. 1991;229:67–71.

    Article  CAS  Google Scholar 

  57. Christensen SB, Ericsson UB, Janzon L, et al. Influence of cigarette smoking on goiter formation, thyroglobulin, and thyroid hormone levels in women. J Clin Endocrinol Metab. 1984;58:615–8.

    Article  PubMed  CAS  Google Scholar 

  58. Eden S, Jagenburg R, Lindstedt G, et al. Thyroregulatory changes associated with smoking in 70-year-old men. Clin Endocrinol. 1984;21:605–10.

    Article  CAS  Google Scholar 

  59. Karakaya A, Tuncel N, Alptuna G, et al. Influence of cigarette smoking on thyroid hormone levels. Hum Toxicol. 1987;6:507–9.

    Article  PubMed  CAS  Google Scholar 

  60. Ron E. Thyroid cancer. Cancer epidemiology prevention. 2nd ed. New York: Oxford University Press; 1996. p. 1000–21.

    Google Scholar 

  61. Baron JA, La Vecchia C, Levi F. The antiestrogenic effect of cigarette smoking in women. Am J Obstet Gynecol. 1990;162:502–14.

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge the technical staff of operation theater of Department of General Surgery especially Mr. Abdul Ahad who helped us in procuring the tissue samples. Our thanks are also due to the Head and faculty members of Department of Nuclear Medicine who helped us in procuring the blood samples. The authors also acknowledge the timely and precious help of Dr. Rayes Ahmad Dar of Department of Statistics, Sher-I-Kashmir Institute of Medical Sciences.

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Authors and Affiliations

  1. Department of Clinical Biochemistry, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, 190011, India

    Mosin S. Khan, Mohammad Iqbal, Nighat P. Khan & Syed Mudassar

  2. Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, 190011, India

    Arshad A. Pandith

  3. Department of Biotechnology, University of Kashmir, Srinagar, Kashmir, 190006, India

    Mahboob ul Hussain

  4. Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, 190011, India

    Khurshid A. Wani

  5. Department of Endocrinology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, 190011, India

    Shariq R. Masoodi

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  1. Mosin S. Khan
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Khan, M.S., Pandith, A.A., ul Hussain, M. et al. Lack of mutational events of RAS genes in sporadic thyroid cancer but high risk associated with HRAS T81C single nucleotide polymorphism (case–control study). Tumor Biol. 34, 521–529 (2013). https://doi.org/10.1007/s13277-012-0577-y

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