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Relationship between TSHR, BRAF and PIK3CA gene copy number variations and thyroid nodules

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Abstract

Purpose

This study aims to investigate the relationship between the TSHR, BRAF, and PIK3CA gene copy number variations (CNVs) and thyroid nodules by analyzing gene CNVs, and to explore the interaction between iodine status and the above genes CNVs in the occurrence of thyroid nodules.

Methods

Three hundred and ninety-five subjects were selected from 3 regions with different iodine status in Shanxi Province of China, including 192 patients with thyroid nodules and 203 healthy controls. The basic information about subjects had been obtained through a questionnaire. B ultrasound was utilized to check thyroid nodules. Blood and urine samples were harvested to detect the thyroid function and urinary iodine concentration. Real-time quantitative polymerase chains reaction (RT-PCR) served to detect CNVs in DNA from human blood.

Results

There was an association between TSHR gene CNV and thyroid nodules (χ2 = 8.403, P = 0.004). The prevalence of BRAF and PIK3CA gene CNVs was not statistically significant between the case group and the control group. Differences in the TSHR gene CNV rates for cases of the 3 areas were statistically significant (χ2 = 10.072, P = 0.007). No statistical difference in the prevalence rates of the 3 genes CNVs between diverse characteristics of thyroid nodules was observed. UIC > 300 μg/L (OR = 1.74, 95% CI: 1.02–2.96, P = 0.041) and TSHR gene CNV (OR = 3.53, 95% CI: 1.40–8.92, P = 0.008) were risk factors for thyroid nodules. There was no significant interaction between the UIC and the examined genes CNVs.

Conclusions

TSHR gene CNV and high urinary iodine levels can increase the risk of thyroid nodules. But the interactions between the 3 above genes CNVs and iodine nutrition were not found in the occurrence of thyroid nodules.

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References

  1. B.R. Haugen, E.K. Alexander, K.C. Bible, G.M. Doherty, S.J. Mandel, Y.E. Nikiforov et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26(1), 1–133 (2016). https://doi.org/10.1089/thy.2015.0020

    Article  PubMed  PubMed Central  Google Scholar 

  2. L.R. Remonti, C.K. Kramer, C.B. Leitao, L.C. Pinto, J.L. Gross, Thyroid ultrasound features and risk of carcinoma: a systematic review and meta-analysis of observational studies. Thyroid 25(5), 538–550 (2015). https://doi.org/10.1089/thy.2014.0353

    Article  PubMed  PubMed Central  Google Scholar 

  3. Y. Yao, X. Chen, S. Wu, L. Guo, H. Zhang, Q. Zhu et al. Thyroid nodules in centenarians: prevalence and relationship to lifestyle characteristics and dietary habits. Clin. Inter. Aging 13, 515–522 (2018). https://doi.org/10.2147/CIA.S162425

    Article  Google Scholar 

  4. G. Popoveniuc, J. Jonklaas, Thyroid nodules. Med Clin. North Am. 96(2), 329–349 (2012). https://doi.org/10.1016/j.mcna.2012.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. L. Giovanella, F. D’Aurizio, A. Campenni, R.M. Ruggeri, S. Baldari, F.A. Verburg et al. Searching for the most effective thyrotropin (TSH) threshold to rule-out autonomously functioning thyroid nodules in iodine deficient regions. Endocrine 54(3), 757–761 (2016). https://doi.org/10.1007/s12020-016-1094-3

    Article  CAS  PubMed  Google Scholar 

  6. J. Song, S.R. Zou, C.Y. Guo, J.J. Zang, Z.N. Zhu, M. Mi et al. Prevalence of thyroid nodules and its relationship with iodine status in Shanghai: a population-based study. Biomed. Environ. Sci. 29(6), 398–407 (2016). https://doi.org/10.3967/bes2016.052

    Article  CAS  PubMed  Google Scholar 

  7. J. Yi, Y. Dai, Y. Zhang, F. He,, Influencing factors of iodine nutrition and thyroid nodules among residents in Zhoushan. J. Preventive Med. 30(6), 600–602 (2018). https://doi.org/10.19485/j.cnki.issn2096-5087.2018.06.015

    Article  Google Scholar 

  8. Y. Tian, J. Liu, X. Tang, S. Fu, L. Ma, W. Sun, Study on the relationship between adults iodine nutritional status and TSH, thyroid autoantibodies and thyroid nodules in Gansu. Acta Nutrimenta Sin. 41(3), 248–252 (2019). https://doi.org/10.3969/j.issn.0512-7955.2019.03.009

    Article  Google Scholar 

  9. S.Y. Mon, G. Riedlinger, C.E. Abbott, R. Seethala, N.P. Ohori, M.N. Nikiforova et al. Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid-stimulating hormone receptor gene mutations. Diagn. Cytopathol. 46(5), 369–377 (2018). https://doi.org/10.1002/dc.23915

    Article  PubMed  Google Scholar 

  10. Y. Dai, F. Zhang, Z. Jiang, J. Ye, X. Long, W. Lan et al. Correlation between mutations in the tenth exon gene of thyroid stimulating hormone receptor and thyroid cancer. Guangdong Med. J. 29(003), 382–384 (2008). https://doi.org/10.3969/j.issn.1001-9448.2008.03.014.

    Article  CAS  Google Scholar 

  11. Y.E. Nikiforov, M.N. Nikiforova, Molecular genetics and diagnosis of thyroid cancer. Nat. Rev. Endocrinol. 7(10), 569–580 (2011). https://doi.org/10.1038/nrendo.2011.142

    Article  CAS  PubMed  Google Scholar 

  12. C. Halaszlaki, B. Tobias, B. Balla, J.P. Kosa, J. Horanyi, E. Bolony et al. Predictive value of somatic mutations for the development of malignancy in thyroid nodules by cytopathology. Endocr. Pr. 22(9), 1081–1087 (2016). https://doi.org/10.4158/EP151057.OR

    Article  Google Scholar 

  13. M. Xing, Genetic alterations in the phosphatidylinositol-3 kinase/Akt pathway in thyroid cancer. Thyroid 20(7), 697–706 (2010). https://doi.org/10.1089/thy.2010.1646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. E.R. Gamazon, B.E. Stranger, The impact of human copy number variation on gene expression. Brief. Funct. Genom. 14(5), 352–357 (2015). https://doi.org/10.1093/bfgp/elv017

    Article  CAS  Google Scholar 

  15. S.H. Almal, H. Padh, Implications of gene copy-number variation in health and diseases. J. Hum. Genet 57(1), 6–13 (2012). https://doi.org/10.1038/jhg.2011.108

    Article  CAS  PubMed  Google Scholar 

  16. J. Abubaker, Z. Jehan, P. Bavi, M. Sultana, S. Al-Harbi, M. Ibrahim et al. Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. J. Clin. Endocrinol. Metab. 93(2), 611–618 (2008). https://doi.org/10.1210/jc.2007-1717

    Article  CAS  PubMed  Google Scholar 

  17. M. Kumorowicz-Czoch, A. Madetko-Talowska, D. Tylek-Lemanska, J.J. Pietrzyk, J. Starzyk, Identification of deletions in children with congenital hypothyroidism and thyroid dysgenesis with the use of multiplex ligation-dependent probe amplification. J. Pediatr. Endocrinol. Metab. 28(1-2), 171–176 (2015). https://doi.org/10.1515/jpem-2014-0040

    Article  CAS  PubMed  Google Scholar 

  18. X. Jin, Y. Guan, H. Shen, Y. Pang, L. Liu, Q. Jia et al. Copy number variation of immune-related genes and their association with iodine in adults with autoimmune thyroid diseases. Int J. Endocrinol. 2018, 1705478 (2018). https://doi.org/10.1155/2018/1705478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Y. Guan, L. Liu, Q. Jia, X. Jin, Y. Pang, F. Meng et al. The role of cell growth-related gene copy number variation in autoimmune thyroid disease. Biol Trace Elem Res. (2019). https://doi.org/10.1007/s12011-019-01880-7

  20. Y. Pang, Y. Guan, X. Jin, H. Shen, L. Liu, Q. Jia et al. Association of TSHR gene copy number variation with TSH abnormalities. Biol. Trace Elem. Res. 186(1), 85–90 (2018). https://doi.org/10.1007/s12011-018-1300-7

    Article  CAS  PubMed  Google Scholar 

  21. Y. Lin. The study of the relationship between iodine nutritional status and thyroid disease in adults in Shanxi. (Shanxi Medical University, China, 2017)

  22. L. A. Aday. Deciding how many will be in sample. In Designing and conducting health surveys, (John Wiley & Sons Inc, San Francisco, CA, 2006), pp. 154–193

  23. M. Gao, Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Chinese J. Clin. Oncol. 000(017), 1249–1272 (2012). https://doi.org/10.3969/j.issn.1000-8179.2012.17.001

    Article  Google Scholar 

  24. Y. Zhang, Y. Yan, L. Liu, Y. Sun, W. Li, J. Hua et al. Determination of iodine in urine-Part 1: As3+-Ce4+ catalytic spectrophotometry (WS/T107.1-2016). Health Standard of China (2016)

  25. G. Wu, E. Mambo, Z. Guo, S. Hu, X. Huang, S. M. Gollin et al. Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J. Clin. Endocrinol. Metab. 90(8), 4688–4693 (2005). https://doi.org/10.1210/jc.2004-2281

  26. K.J. Livak, T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4), 402–408 (2001). https://doi.org/10.1006/meth.2001.1262

    Article  CAS  Google Scholar 

  27. L. Zhang, Y. Zhou, C. Cheng, H. Cui, L. Cheng, P. Kong et al. Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma. Am. J. Hum. Genet 96(4), 597–611 (2015). https://doi.org/10.1016/j.ajhg.2015.02.017

    Article  CAS  PubMed  Google Scholar 

  28. WHO/UNICEF/ICCIDD: assessment of iodine deficiency disorders and monitoring their elimination, a guide for program managers, 3rd ed. (WHO/UNICEF/ICCIDD, 2007) p. 33

  29. Y. Du, Y. Gao, F. Meng, S. Liu, Z. Fan, J. Wu et al. Iodine deficiency and excess coexist in china and induce thyroid dysfunction and disease: a cross-sectional study. PLoS ONE 9(11), e111937 (2014). https://doi.org/10.1371/journal.pone.0111937

    Article  CAS  PubMed  Google Scholar 

  30. X. Chen, A. Pospective, Study of the effect of different iodine intake on goiter and thyroid nodule. China Foreign Med. Treat. 037(020), 44–46 (2018). https://doi.org/10.16662/j.cnki.1674-0742.2018.20.044

    Article  Google Scholar 

  31. F. Hu, X. Teng, W. Teng, H. Guan, F. Yang, T. Gao et al. A comparative epidemic study of goiter and thyroid nodules in areas with different iodine intake. Chin. J. Endemiol. 21(006), 464–467 (2002). https://doi.org/10.3760/cma.j.issn.1000-4955.2002.06.011

    Article  Google Scholar 

  32. W.L. Liao, L. Wan, T.Y. Wang, C.C. Chen, S.S. Tse, C.H. Lu et al. Association of TLR7 and TSHR copy number variation with Graves’ disease and Graves’ ophthalmopathy in Chinese population in Taiwan. BMC Ophthalmol. 14, 15 (2014). https://doi.org/10.1186/1471-2415-14-15

    Article  CAS  PubMed  Google Scholar 

  33. S. Sancak, H. Jaeschke, F. Eren, O. Tarcin, B. Guellueoglu, L.S. Sen et al. High prevalence of TSHR/Gsalpha mutation-negative clonal hot thyroid nodules (HNs) in a Turkish cohort. Horm. Metab. Res 43(8), 562–568 (2011). https://doi.org/10.1055/s-0031-1280829

    Article  PubMed  Google Scholar 

  34. C.J. Tsai, R. Nussinov, Allosteric activation of RAF in the MAPK signaling pathway. Curr. Opin. Struct. Biol. 53, 100–106 (2018). https://doi.org/10.1016/j.sbi.2018.07.007

    Article  CAS  PubMed  Google Scholar 

  35. R. Ciampi, Z. Zhu, Y.E. Nikiforov, BRAF copy number gains in thyroid tumors detected by fluorescence in situ hybridization. Endocr. Pathol. 16(2), 99–105 (2005). https://doi.org/10.1385/ep:16:2:099

    Article  CAS  PubMed  Google Scholar 

  36. L. Santarpia, A.K. El-Naggar, G.J. Cote, J.N. Myers, S.I. Sherman, Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 93(1), 278–284 (2008). https://doi.org/10.1210/jc.2007-1076

    Article  CAS  PubMed  Google Scholar 

  37. R.B. Schechter, M. Nagilla, L. Joseph, P. Reddy, A. Khattri, S. Watson et al. Genetic profiling of advanced radioactive iodine-resistant differentiated thyroid cancer and correlation with axitinib efficacy. Cancer Lett. 359(2), 269–274 (2015). https://doi.org/10.1016/j.canlet.2015.01.024

    Article  CAS  PubMed  Google Scholar 

  38. P. Yin. The relationship between PI3K/Akt signal transduction pathway and thyroid nodule. Master’s dissertation (Tianjin Medical University, China, 2010)

  39. M.P. Rayman, Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease. Proc. Nutr. Soc. 78(1), 34–44 (2019). https://doi.org/10.1017/S0029665118001192

    Article  CAS  PubMed  Google Scholar 

  40. D. Yildirim, B. Gurses, B. Gurpinar, B. Ekci, B. Colakoglu, A. Kaur, Nodule or pseudonodule? Differentiation in Hashimoto’s thyroiditis with sonoelastography. J. Int. Med. Res. 39(6), 2360–2369 (2011). https://doi.org/10.1177/147323001103900636

    Article  CAS  PubMed  Google Scholar 

  41. A. Prete, R.M. Paragliola, S.M. Corsello, Iodine supplementation: usage “with a Grain of Salt”. Int. J. Endocrinol. 2015, 312305 (2015). https://doi.org/10.1155/2015/312305

    Article  PubMed  PubMed Central  Google Scholar 

  42. N.A. Georgopoulos, G.P. Sykiotis, A. Sgourou, A. Papachatzopoulou, K.B. Markou, V. Kyriazopoulou et al. Autonomously functioning thyroid nodules in a former iodine-deficient area commonly harbor gain-of-function mutations in the thyrotropin signaling pathway. Eur. J. Endocrinol. 149(4), 287–292 (2003). https://doi.org/10.1530/eje.0.1490287

    Article  CAS  PubMed  Google Scholar 

  43. T.E. Angell, R. Maurer, Z. Wang, M.I. Kim, C.A. Alexander, J.A. Barletta et al. A cohort analysis of clinical and ultrasound variables predicting cancer risk in 20,001 consecutive thyroid nodules. J. Clin. Endocrinol. Metab. 104(11), 5665–5672 (2019). https://doi.org/10.1210/jc.2019-00664

    Article  PubMed  Google Scholar 

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Acknowledgements

We are grateful for the assistance provided by the Institute for Prevention and Treatment of Endemic Disease of Shanxi Province for collecting epidemiologic data and samples, and contributions and support from all participants.

Funding

This study was supported by grants from the National Natural Science Foundation of China (81573098).

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Author notes

  1. These authors contributed equally: Xiaoli Shi, Mengying Qu

Authors and Affiliations

  1. Centre for Endemic Disease Control, Chinese Centre for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang, China

    Xiaoli Shi, Mengying Qu, Xing Jin, Lixiang Liu, Fangang Meng & Hongmei Shen

  2. Department of Medical Administration, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Xiaoli Shi

  3. Department of Epidemiology, School of Public Health, Dalian Medical University, Dalian, China

    Xing Jin

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  1. Xiaoli Shi
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Contributions

HS and XS designed this research. HS, LL, XJ, XS and FM conducted the research. XS analyzed the data and MQ wrote the paper. HS had primary responsibility for the final content. All authors read and approved the final manuscript for submission.

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Correspondence to Hongmei Shen.

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The authors declare that they have no conflict of interest.

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All the procedures used in this experiment were reviewed and approved by the biomedical research ethics committee of Harbin Medical University.

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Informed consent was obtained from all individual participants included in the study.

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Shi, X., Qu, M., Jin, X. et al. Relationship between TSHR, BRAF and PIK3CA gene copy number variations and thyroid nodules. Endocrine 73, 116–124 (2021). https://doi.org/10.1007/s12020-020-02587-9

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