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Frequency and Role of CDKN2A Deletion in High-Risk Pituitary Neuroendocrine Tumors

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Abstract

The underlying mechanisms of aggressive pituitary neuroendocrine tumors (pitNETs) are still unclear. The p16 protein, encoded by the CDKN2A tumor suppressor gene on chromosome 9p21, is commonly reported to be lost in numerous types of cancer. For this reason, this study examined to examine the status of homozygous deletion of CDKN2A in high-risk pitNETs. Thirty-eight high-risk pitNETs (30 male, 8 female) were analyzed for CDKN2A deletion by fluorescent in situ hybridization (FISH). Demographic characteristics such as sex, patient age at operation, and sellar magnetic resonance imaging findings including tumor size and invasion status were recorded. The frequency of CDKN2A homozygous deletion by FISH was 3/38 (7.89%) in the high-risk pitNET group. All of these three cases with CDKN2A homozygous deletion were invasive densely granulated lactotroph tumors (p = 0.000). CDKN2A deletion was not correlated with patient age, sex, cavernous sinus invasion (CSI), and tumor size (p > 0.05). The Ki-67 proliferation index was significantly correlated with CDKN2A homozygous deletion (p = 0.003). The mean Ki-67 proliferation index was 10.7% in pitNETs with CDKN2A homozygous deletion and the Ki-67 proliferation index in the whole study group was 4.1%. CSI was significantly correlated with the morphofunctional tumor types including lactotroph tumor, invasive null cell tumor, and invasive gonadotroph tumor (p = 0.021). These findings suggest a close correlation between inactivation of p16 gene and invasive lactotroph tumors. Further investigations are needed to expand on the mechanism of p16 (CDKN2A) gene deletion in high-risk pitNETs.

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References

  1. Colao A, Grasso LF, Pivonello R, Lombardi G.: Therapy of aggressive pituitary tumors. Expert Opin Pharmaco. 12:1561–1570 (2011)

    Article  CAS  Google Scholar 

  2. Daly AF, Jaffrain-Rea ML, Ciccarelli A, Valdes-Socin H, Rohmer V, Tamburrano G, Borson-Chazot C, Estour B, Ciccarelli E, Brue T, Ferolla P, Emy P, Colao A, de Menis E, Lecomte P, Penfornis F, Delemer B, Bertherat J, Wémeau JL, de Herder W, Archambeaud F, Stevenaert A, Calender A, Murat A, Cavagnini F, Beckers A: Clinical characterization of familial isolated pituitary adenomas. J Clin Endocrinol Metab 91: 3316–3323 (2006)

    Article  CAS  Google Scholar 

  3. Theodros D, Patel M, Ruzevick J, Lim M, Bettegowda C.: Pituitary adenomas: historical perspective, surgical management and future directions. CNS Oncol. 4(6):411–429 (2015)

    Article  CAS  Google Scholar 

  4. Mete O, Lopes MB. Overview of the 2017 WHO Classification of Pituitary Tumors. Endocr Pathol Sep;28(3):228–243 (2017)

    Article  CAS  Google Scholar 

  5. Inoshita N, Nishioka H.: The 2017 WHO classification of pituitary adenoma: overview and comments. Brain Tumor Pathol. Apr;35(2):51–56 (2018)

    Article  CAS  Google Scholar 

  6. Dworakowska D, Grossman AB.:Aggressive and malignant pituitary tumours: state-of-the-art. Endocr Relat Cancer. (2018). https://doi.org/10.1530/ERC-18-0228

    Article  CAS  Google Scholar 

  7. Shapiro GI.: Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 24: 1770–1783 (2006)

    Article  CAS  Google Scholar 

  8. Ogino A, Yoshino A, Katayama Y, Watanabe T, Ota T, Komine C, Yokoyama T, Fukushima T: The p15(INK4b)/p16(INK4a)/RB1 pathway is frequently deregulated in human pituitary adenomas. J Neuropathol Exp Neurol 64:398–403 (2005)

    Article  CAS  Google Scholar 

  9. Roussel MF.: The INK4 family of cell cycle inhibitors in cancer. Oncogene. 18: 5311–5317 (1999)

    Article  CAS  Google Scholar 

  10. Woloschak M, Yu A, Post KD.: Frequent inactivation of the p16 gene in human pituitary tumours by gene methylation. Mol Carcinogen 19: 221–224 (1997)

    Article  CAS  Google Scholar 

  11. Seemann N, Kuhn D, Wrocklage C, Keyvani K, Hackl W, Buchfelder M, Fahlbusch R, Paulus W: CDKN2A /p16 inactivation is related to pituitary adenoma type and size. J Pathol 193: 491–497 (2001)

    Article  CAS  Google Scholar 

  12. Mooney MA, Hardesty DA, Sheehy JP, Bird CR, Chapple K, et al.: Rater Reliability of the Hardy Classification for Pituitary Adenomas in the Magnetic Resonance Imaging Era. J Neurol Surg B Skull Base. (2017). https://doi.org/10.1055/s-0037-1603649

    Article  Google Scholar 

  13. Lloyd RV, Osamura RY, Kloppel G, Rosai J.: WHO classification of tumours of endocirne organs, 4th edn. International Agency for Research on Cancer, Lyon 3. (2017)

    Google Scholar 

  14. Hasanov R, Aydoğan Bİ, Kiremitçi S, Erden E, Güllü S.: The Prognostic Roles of the Ki-67 Proliferation Index, P53 Expression, Mitotic Index, and Radiological Tumor Invasion in Pituitary Adenomas. Endocr Pathol. 30: 49-55 (2019). https://doi.org/10.1007/s12022-018-9563-2.

    Article  CAS  PubMed  Google Scholar 

  15. Mastronardi L, Guiducci A, Puzzilli F.: Lack of correlation between Ki-67 labelling index and tumor size of anterior pituitary adenomas. BMC Cancer 1:12 (2001)

    Article  CAS  Google Scholar 

  16. Peker S, Kurtkaya-Yapıcıer O, Kılıc T, Pamir MN.: Microsurgical anatomy of the lateral walls of the pituitary fossa. Acta Neurochir (Wien). 147(6):641–648; discussion 649. Epub 2005 Apr 4. (2005).

    Article  CAS  Google Scholar 

  17. Sclon MF, Peters JR, Thomas JP, Richards SH, Morton WH, et al.: Management of selected patients with hyperprolactinaemia by partial hypophysectomy. Br Med J (Clin Res Ed) 291:1547–1550 (1985)

    Article  Google Scholar 

  18. Serri O, Rasio E, Beauregard H, Hardy J, Somma M.: Recurrence of hyperprolactinemia after selective transsphenoidal adenomectomy in women with prolactinoma. N Engl J. Med 309:280–283 (1983)

    Article  CAS  Google Scholar 

  19. Congxin Dai, Ming Feng, Xiaohai Liu, Sihai Ma, Bowen Sun, et al.: Refractory pituitary adenoma: a novel classification for pituitary tumors. Oncotarget. Dec 13; 7(50): 83657–83668 (2016)

    Article  Google Scholar 

  20. Lu JG, Huang ZQ, Wu JS, Wang Q, Ma QJ, et al.: Significance of tumor suppressor gene p16 expression in primary biliary cancer. Shijie Huaren Xiaohua Zazhi. 8: 638–640 (2000)

    CAS  Google Scholar 

  21. Serrano M, Hannon GJ, Beach D.: A new regulatorymotif in cellcycle control causing specific ihhibition of cyclin D/CDK4. Nature. 366: 704–707 (1993)

    Article  CAS  Google Scholar 

  22. Tam KW, Zhang W, Soh J, Stastny V, Chen M, Marconett CN, et al: CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small-cell lung cancer. J Thorac Oncol 8: 1378–1388 (2013)

    Article  CAS  Google Scholar 

  23. Riehmer V, Gietzelt J, Beyer U, Hentschel B,: Westphal M, Schackert G, Sabel MC, Radlwimmer B, Pietsch T, Reifenberger G, et al: Genomic profiling reveals distinctive molecular relapse patterns in IDH1/2 wild-type glioblastoma. Genes Chromosomes Cancer 53: 589–605 (2014)

    Article  CAS  Google Scholar 

  24. Shi ZZ, Shang L, Jiang YY, Hao JJ, Zhang Y, Zhang TT, Lin DC, Liu SG, Wang BS, Gong T, Zhan QM, Wang MR: Consistent and differential genetic aberrations between esophageal dysplasia and squamous cell carcinoma detected by array comparative genomic hybridization. Clin Cancer Res 19: 5867–5878 (2013)

    Article  CAS  Google Scholar 

  25. Negrini S, Gorgoulis VG, Halazonetis TD: Genomic instability - an evolving hallmark of cancer. Nat Rev Mol Cell Biol 11: 220–228 (2010)

    Article  CAS  Google Scholar 

  26. Caccavelli L, Feron F, Morange I, Rouer E, Benarous R, Dewailly D, Jaquet P, Kordon C, Enjalbert A: Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas. Neuroendocrinology. 60:314–322 (1994)

    Article  CAS  Google Scholar 

  27. Liu W, Zahr RS, McCartney S, Cetas JS, Dogan A, et al.: Clinical outcomes in male patients with lactotroph adenomas who required pituitary surgery: a retrospective single center study. Pituitary. Oct; 21(5):454–462 (2018)

    Article  Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Endocrinology, Acibadem University School of Medicine, Istanbul, Turkey

    Müjdat Kara

  2. Altunizade Acıbadem Hastanesi, Altunizade Mahallesi, Yurtcan Sokagi No:1, Uskudar, 34662, Istanbul, Turkey

    Müjdat Kara

  3. Department of Pathology, Acibadem University School of Medicine, Istanbul, Turkey

    Fatma Tokat & Ayça Ersen Danyeli

  4. Department of Neurosurgery, Acibadem University School of Medicine, Istanbul, Turkey

    M. Necmettin Pamir

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  1. Müjdat Kara
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  2. Fatma Tokat
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Correspondence to Müjdat Kara.

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The Ethics Committee of Acıbadem Institutional Review Board approved this study and waived the requirement for informed consent.

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Kara, M., Tokat, F., Pamir, M.N. et al. Frequency and Role of CDKN2A Deletion in High-Risk Pituitary Neuroendocrine Tumors. Endocr Pathol 31, 166–173 (2020). https://doi.org/10.1007/s12022-020-09609-2

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