Identification of a novel HRAS variant and its association with papillary thyroid carcinoma

  • Authors:
    • Rui Dou
    • Lili Zhang
    • Tingxia Lu
    • Dong Liu
    • Fang Mei
    • Jian Huang
    • Linxue Qian
  • View Affiliations

  • Published online on: January 17, 2018     https://doi.org/10.3892/ol.2018.7818
  • Pages: 4511-4516
Metrics: HTML 0 views | PDF 0 views     Cited By (CrossRef): 0 citations

Abstract

HRas proto‑oncogene (HRAS) is one of the most commonly mutated genes in thyroid cancer, with mutations frequently occurring in the follicular and Hurthle cell subtypes. However, the contribution of mutations in HRAS to papillary thyroid carcinoma (PTC) progression and the tall‑cell variant (TCV) is poorly understood. The aim of the present study was to investigate the somatic genetic variants present in HRAS in patients with PTC, and to investigate the association of these mutations with PTC. The present study is a retrospective case‑control study using tumor samples collected from 139 patients with PTC and blood samples from 195 healthy individuals. All patient samples were screened for mutations in ‘hotspot’ regions of HRAS and B‑raf proto‑oncogene (BRAF) by single‑stranded conformational polymorphism analysis, followed by direct sequencing. A novel variant (IVS1‑82del gctgggcctggg) in the HRAS 5'‑untranslated region was identified. There was no difference in age or sex of patients with PTC and the healthy controls; however, the HRAS variant was more frequently detected in PTC tissue than in the healthy control samples (37 vs. 26%, P=0.04). There was no association between the HRAS variant and age, sex, tumor size, encapsulation, multifocality/intra‑thyroidal spread, Tumor‑Node‑Metastasis stage, history of Hashimoto's disease, BRAF V600E mutation or PTC subtype (all P>0.05). There were differences of BRAF V600E distribution among different subtypes (χ2=6.390, P=0.041). HRAS variant co‑occurring with the BRAF V600E mutation accounted for 31.6% of the total number (P=0.196). Therefore, this novel variant of HRAS (IVS1‑82del gctgggcctggg) may be associated with PTC; however, larger scale studies are required to assess the contribution of this novel HRAS variant to PTC progression.

References

1 

Hou P, Bojdani E and Xing M: Induction of thyroid gene expression and radioiodine uptake in thyroid cancer cells by targeting major signaling pathways. J Clin Endocrinol Metab. 95:820–828. 2010. View Article : Google Scholar : PubMed/NCBI

2 

Ron E and Schneider AB: Thyroid CancerCancer Epidemiology and Prevention. Schottenfeld D and Fraumeni JF: Oxford University Press; New York: 2006, View Article : Google Scholar

3 

Rahbari R, Zhang L and Kebebew E: Thyroid cancer gender disparity. Future Oncol. 6:1771–1779. 2010. View Article : Google Scholar : PubMed/NCBI

4 

Aschebrook-Kilfoy B, Ward MH, Sabra MM and Devesa SS: Thyroid cancer incidence patterns in the United States by histologic type, 1992–2006. Thyroid. 21:125–134. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Schneider DF and Chen H: New developments in the diagnosis and treatment of thyroid cancer. CA Cancer J Clin. 63:374–394. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Ghossein R and Livolsi VA: Papillary thyroid carcinoma tall cell variant. Thyroid. 18:1179–1181. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Livolsi VA, Albores-Saavedra J, Asa SL, Baloch ZW, Sobrinho-Simoes M, Wenig B, DeLellis RA, Cady B, Mazzaferri EL, Hay I, et al: Papillary CarcinomaPathology and Genetics: Tumours of Endocrine Organs. World Health Organization Classification of Tumours. DeLellis RA, Lloyd RV, Heitz R and Eng C: IARC Press; Lyon: 2004

8 

Kim KB, Cabanillas ME, Lazar AJ, Williams MD, Sanders DL, Ilagan JL, Nolop K, Lee RJ and Sherman SI: Clinical responses to vemurafenib in patients with metastatic papillary thyroid cancer harboring BRAF (V600E) mutation. Thyroid. 23:1277–1283. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Joo JY, Park JY, Yoon YH, Choi B, Kim JM, Jo YS, Shong M and Koo BS: Prediction of occult central lymph node metastasis in papillary thyroid carcinoma by preoperative BRAF analysis using fine-needle aspiration biopsy: A prospective study. J Clin Endocrinol Metab. 97:3996–4003. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Kurtulmus N, Duren M, Ince U, Cengiz Yakicier M, Peker O, Aydin O, Altiok E, Giray S and Azizlerli H: BRAF (V600E) mutation in Turkish patients with papillary thyroid cancer: Strong correlation with indicators of tumor aggressiveness. Endocrine. 42:404–410. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Aksamitiene E, Kiyatkin A and Kholodenko BN: Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: A fine balance. Biochem Soc Trans. 40:139–146. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Xing M: Genetic alterations in the phosphatidylinositol-3 kinase/Akt pathway in thyroid cancer. Thyroid. 20:697–706. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Nikiforov YE and Nikiforova MN: Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 7:569–580. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Zhu Z, Gandhi M, Nikiforova MN, Fischer AH and Nikiforov YE: Molecular profile and clinical-pathologic features of the follicular mutation of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol. 120:71–77. 2003. View Article : Google Scholar : PubMed/NCBI

15 

Park JY, Kim WY, Hwang TS, Lee SS, Kim H, Han HS, Lim SD, Kim WS, Yoo YB and Park KS: BRAF and RAS mutations in follicular mutation of papillary thyroid carcinoma. Endocr Pathol. 24:69–76. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Rivera M, Ricarte-Filho J, Knauf J, Shaha A, Tuttle M, Fagin JA and Ghossein RA: Molecular genotyping of papillary thyroid carcinoma follicular mutation according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. Mod Pathol. 23:1191–1200. 2010. View Article : Google Scholar : PubMed/NCBI

17 

Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, Biddinger PW and Nikiforov YE: Correlation between genetic alterations and microscopic features, clinical manifestations and prognostic characteristics of thyroid papillary carcinomas. Am J Surg Pathol. 30:216–222. 2006. View Article : Google Scholar : PubMed/NCBI

18 

Liu RT, Hou CY, You HL, Huang CC, Hock-Liew, Chou FF, Wang PW and Cheng JT: Selective occurrence of ras mutations in benign and malignant thyroid follicular neoplasms in Taiwan. Thyroid. 14:616–621. 2004. View Article : Google Scholar : PubMed/NCBI

19 

Huang J, Pang J, Watanabe T, Ng HK and Ohgaki H: Whole genome amplification for array comparative genomic hybridization using DNA extracted from formalin-fixed, paraffin-embedded histological sections. J Mol Diagn. 11:109–116. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Huang J, Zhao YP, Li Q, Zhang JX, Wang Y and Zhang B: Association of single nucleotide polymorphisms of NBS1 gene with genetic susceptibility to primary liver cancer in a Chinese Han population. Prog Biochem Biophys. 39:678–686. 2012. View Article : Google Scholar

21 

Huang J, Grotzer MA, Watanabe T, Hewer E, Pietsch T, Rutkowski S and Ohgaki H: Mutations in the Nijmegen breakage syndrome gene in medulloblastomas. Clin Cancer Res. 14:4053–4058. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Qing W, Fang WY, Ye L, Shen LY, Zhang XF, Fei XC, Chen X, Wang WQ, Li XY, Xiao JC and Ning G: Density of tumor-associated macrophages correlates with lymph node metastasis in papillary thyroid carcinoma. Thyroid. 22:905–910. 2012. View Article : Google Scholar : PubMed/NCBI

23 

Lloyd RV, Buehler D and Khanafshar E: Papillary thyroid carcinoma mutation. Head Neck Pathol. 5:51–56. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Okayasu I, Fujiwara M, Hara Y, Tanaka Y and Rose NR: Association of chronic lymphocytic thyroiditis and thyroid papillary carcinoma. A study of surgical cases among Japanese and white and African Americans. Cancer. 76:2312–2318. 1995. View Article : Google Scholar : PubMed/NCBI

25 

Hiromatsu Y, Satoh H and Amino N: Hashimoto's thyroiditis: History and future outlook. Hormones (Athens). 12:12–18. 2013.PubMed/NCBI

26 

Long J, Wang Y, Li M, Tong WM, Jia JD and Huang J: Correlation of TP53 mutations with HCV positivity in hepatocarcinogenesis: Identification of a novel TP53 microindel in hepatocellular carcinoma with HCV infection. Oncol Rep. 30:119–124. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Huang MD, Chen XF, Xu G, Wu QQ, Zhang JH, Chen GF, Cai Y and Qi FZ: Genetic variation in the NBS1 gene is associated with hepatic cancer risk in a Chinese population. DNA Cell Biol. 31:678–682. 2012. View Article : Google Scholar : PubMed/NCBI

28 

Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE and Fagin JA: 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. 63:1454–1457. 2003.PubMed/NCBI

29 

Soares P, Trovisco V, Rocha AS, Lima J, Castro P, Preto A, Máximo V, Botelho T, Seruca R and Sobrinho-Simões M: BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene. 22:4578–4580. 2003. View Article : Google Scholar : PubMed/NCBI

30 

Frattini M, Ferrario C, Bressan P, Balestra D, De Cecco L, Mondellini P, Bongarzone I, Collini P, Gariboldi M, Pilotti S, et al: Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. Oncogene. 23:7436–7440. 2004. View Article : Google Scholar : PubMed/NCBI

31 

Dockhorn-Dworniczak B, Caspari S, Schroder S, Bocker W and Dworniczak B: Demonstration of activated oncogenes of the ras family in human thyroid tumors using the polymerase chain reaction. Verh Dtsch Ges Pathol. 74:415–418. 1990.PubMed/NCBI

32 

Schulten HJ, Al-Maghrabi J, Al-Ghamdi K, Salama S, Al-Muhayawi S, Chaudhary A, Hamour O, Abuzenadah A, Gari M and Al-Qahtani M: Mutational screening of RET, HRAS, KRAS, NRAS, BRAF, AKT1 and CTNNB1 in medullary thyroid carcinoma. Anticancer Res. 31:4179–4183. 2011.PubMed/NCBI

33 

Rivera M, Ricarte-Filho J, Tuttle RM, Ganly I, Shaha A, Knauf J, Fagin J and Ghossein R: Molecular, morphologic and outcome analysis of thyroid carcinomas according to degree of extrathyroid extension. Thyroid. 20:1085–1093. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Fujita J, Yoshida O, Yuasa Y, Rhim JS, Hatanaka M and Aaronson SA: Ha-ras oncogenes are activated by somatic alterations in human urinary tract tumours. Nature. 309:464–466. 1984. View Article : Google Scholar : PubMed/NCBI

35 

Kreimer-Erlacher H, Seidl H, Back B, Kerl H and Wolf P: High mutation frequency at Ha-ras exons 1–4 in squamous cell carcinomas from PUVA-treated psoriasis patients. Photochem Photobiol. 74:323–330. 2001. View Article : Google Scholar : PubMed/NCBI

36 

Sathyan KM, Nalinakumari KR, Abraham T and Kannan S: Influence of single nucleotide polymorphisms in H-Ras and cyclin D1 genes on oral cancer susceptibility. Oral Oncol. 42:607–613. 2006. View Article : Google Scholar : PubMed/NCBI

37 

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

38 

Zhang Y, Jin M, Liu B, Ma X, Yao K, Li Q and Chen K: Association between H-RAS T81C genetic polymorphism and gastrointestinal cancer risk: A population based case-control study in China. BMC Cancer. 8:2562008. View Article : Google Scholar : PubMed/NCBI

39 

Castro P, Soares P, Gusmão L, Seruca R and Sobrinho-Simoes M: H-RAS 81 polymorphism is significantly associated with aneuploidy in follicular tumors of the thyroid. Oncogene. 25:4620–4627. 2006. View Article : Google Scholar : PubMed/NCBI

40 

Esapa CT, Johnson SJ, Kendall-Taylor P, Lennard TW and Harris PE: Prevalence of Ras mutations in thyroid neoplasia. Clin Endocrinol (Oxf). 50:529–535. 1999. View Article : Google Scholar : PubMed/NCBI

41 

Zhu Z, Gandhi M, Nikiforova MN, Fischer AH and Nikiforov YE: Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am J Clin Pathol. 120:71–77. 2003. View Article : Google Scholar : PubMed/NCBI

42 

Santarpia L, Myers JN, Sherman SI, Trimarchi F, Clayman GL and El-Naggar AK: Genetic alterations in the RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways in the follicular variant of papillary thyroid carcinoma. Cancer. 116:2974–2983. 2010. View Article : Google Scholar : PubMed/NCBI

43 

Khan MS, Pandith AA, Ul Hussain M, Iqbal M, Khan NP, Wani KA, Masoodi SR and Mudassar S: Lack of mutational events of RAS genes in sporadic thyroid cancer but high risk associated with HRAS T81C single nucleotide polymorphism (case-control study). Tumour Biol. 34:521–529. 2013. View Article : Google Scholar : PubMed/NCBI

44 

Bos JL: ras oncogenes in human cancer: A review. Cancer Res. 49:4682–4689. 1989.PubMed/NCBI

45 

Bos JL: The ras gene family and human carcinogenesis. Mutat Res. 195:255–271. 1988. View Article : Google Scholar : PubMed/NCBI

46 

Hashimoto-Gotoh T, Kikuno R, Takahashi M and Honkawa H: Possible role of the first intron of c-H-ras in gene expression: anti-cancer elements in oncogenes. Anticancer Res. 8:851–859. 1988.PubMed/NCBI

47 

Vasko V, Saji M, Hardy E, Kruhlak M, Larin A, Savchenko V, Miyakawa M, Isozaki O, Murakami H, Tsushima T, et al: Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer. J Med Genet. 41:161–170. 2004. View Article : Google Scholar : PubMed/NCBI

48 

Janku F, Lee JJ, Tsimberidou AM, Hong DS, Naing A, Falchook GS, Fu S, Luthra R, Garrido-Laguna I and Kurzrock R: PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers. PLoS One. 6:e227692011. View Article : Google Scholar : PubMed/NCBI

49 

Zou M, Baitei EY, Alzahrani AS, BinHumaid FS, Alkhafaji D, Al-Rijjal RA, Meyer BF and Shi Y: Concomitant RAS RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma. Thyroid. 24:1256–1266. 2014. View Article : Google Scholar : PubMed/NCBI

50 

Oliveira C, Velho S, Moutinho C, Ferreira A, Preto A, Domingo E, Capelinha AF, Duval A, Hamelin R, Machado JC, et al: KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression. Oncogene. 26:158–163. 2007. View Article : Google Scholar : PubMed/NCBI

51 

Suarez HG, du Villard JA, Severino M, Caillou B, Schlumberger M, Tubiana M, Parmentier C and Monier R: Presence of mutations in all three ras genes in human thyroid tumors. Oncogene. 5:565–570. 1990.PubMed/NCBI

52 

Pilotti S, Collini P, Mariani L, Placucci M, Bongarzone I, Vigneri P, Cipriani S, Falcetta F, Miceli R, Pierotti MA and Rilke F: Insular carcinoma: A distinct de novo entity among follicular carcinomas of the thyroid gland. Am J Surg Pathol. 21:1466–1473. 1997. View Article : Google Scholar : PubMed/NCBI

53 

Ganly I, Ricarte Filho J, Eng S, Ghossein R, Morris LG, Liang Y, Socci N, Kannan K, Mo Q, Fagin JA and Chan TA: Genomic dissection of Hurthle cell carcinoma reveals a unique class of thyroid malignancy. J Clin Endocrinol Metab. 98:E962–E972. 2013. View Article : Google Scholar : PubMed/NCBI

54 

DeLellis RA, Lloyd RV and Heitz PU: World Health Organization Classification of Tumors. Pathology and Genetics: Tumors of Endocrine Organs. IARC Press; Lyon, France: pp. 69–72. 2004

Related Articles

Journal Cover

April 2018
Volume 15 Issue 4

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Dou, R., Zhang, L., Lu, T., Liu, D., Mei, F., Huang, J., & Qian, L. (2018). Identification of a novel HRAS variant and its association with papillary thyroid carcinoma. Oncology Letters, 15, 4511-4516. https://doi.org/10.3892/ol.2018.7818
MLA
Dou, R., Zhang, L., Lu, T., Liu, D., Mei, F., Huang, J., Qian, L."Identification of a novel HRAS variant and its association with papillary thyroid carcinoma". Oncology Letters 15.4 (2018): 4511-4516.
Chicago
Dou, R., Zhang, L., Lu, T., Liu, D., Mei, F., Huang, J., Qian, L."Identification of a novel HRAS variant and its association with papillary thyroid carcinoma". Oncology Letters 15, no. 4 (2018): 4511-4516. https://doi.org/10.3892/ol.2018.7818