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Annals of Surgical Oncology

, Volume 25, Issue 3, pp 801–807 | Cite as

Protein Expression of PTTG1 as a Diagnostic Biomarker in Adrenocortical Carcinoma

  • Minerva Angélica Romero Arenas
  • Timothy G. Whitsett
  • Anna Aronova
  • Samuel A. Henderson
  • Janine LoBello
  • Mouhammed Amir Habra
  • Elizabeth G. Grubbs
  • Jeffrey E. Lee
  • Kanishka Sircar
  • Rasa Zarnegar
  • Theresa Scognamiglio
  • Thomas J. Fahey
  • Nancy D. Perrier
  • Michael J. Demeure
Endocrine Tumors

Abstract

Background

Adrenocortical carcinoma (ACC) has a poor prognosis and there is an unmet clinical need for biomarkers to improve both diagnostic and prognostic assessment. Pituitary-tumor transforming gene (PTTG1) has been shown to modulate cancer invasiveness and response to therapy. The potential role of PTTG1 protein levels in ACC has not been previously addressed. We assessed whether increased nuclear protein expression of PTTG1 distinguished ACCs from adrenocortical adenomas (ACAs).

Methods

Patients with ACC or ACA were identified from prospective tissue banks at two independent institutions. Two tissue microarrays (TMAs) consisting of adrenal specimens from 131 patients were constructed and clinically annotated. Immunohistochemical analysis for PTTG1 and Ki-67 was performed on each TMA.

Results

TMA-1 (n = 80) contained 20 normal adrenals, 20 ACAs, and 40 ACCs, and the validation, TMA-2 (n = 51), consisted of 10 normal adrenals, 14 ACAs, and 27 ACCs. On TMA-1, nuclear staining of PTTG1 was detected in 12 (31%) ACC specimens, while all ACAs and normal adrenal glands were negative for PTTG1. On TMA-2, 20 (74%) of the ACC tumors demonstrated PTTG1 nuclear staining of PTTG1, and 13 (93%) ACA and 4 (44%) normal adrenal glands were negative for PTTG1. ACC tumors with increased PTTG1 protein staining had a significantly higher Ki-67 index (p < 0.001) than those with lower levels of PTTG1.

Conclusions

Increased nuclear protein expression of PTTG1 was observed in malignant adrenal tumors. PTTG1 correlated with Ki-67 in two independent TMAs. PTTG1 is a promising biologic marker in the evaluation of adrenal tumors.

Notes

Acknowledgments

The authors would like to acknowledge Ms. Denái R. Milton for her review of the statistical analyses. Support for Minerva A. Romero Arenas was provided in part by the Golfers Against Cancer and the Dupre Research Fellowship in Surgical Endocrinology. The authors would like to acknowledge support provided by the ATAC Research Fund and the Kristen’s Legacy Fund.

Disclosures

Michael J. Demeure is a paid consultant and has received research support from Arbutus Biopharma Corporation. Minerva Angélica Romero Arenas, Timothy G.Whitsett, Anna Aronova, Samuel A. Henderson, Janine LoBello, Mouhammed Amir Habra, Elizabeth G. Grubbs, Jeffrey E. Lee, Kanishka Sircar, Rasa Zarnegar, Theresa Scognamiglio, Thomas J. Fahey, and Nancy D. Perrier have no conflicts of interest to disclose.

References

  1. 1.
    Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocr Metab. 2006;91(6):2027–37.CrossRefPubMedGoogle Scholar
  2. 2.
    Veerapong J, Lee JE. Adrenal Tumors. In: Feig BW, Ching CD (eds). The MD Anderson Surgical oncology handbook, Fifth Ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.Google Scholar
  3. 3.
    Bilimoria KY, Shen WT, Elaraj D, et al. Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors. Cancer. 2008;113(11):3130–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Grubbs EG, Callender GG, Xing Y, et al. Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane. Ann Surg Oncol. 2010;17:263–70.CrossRefPubMedGoogle Scholar
  5. 5.
    Fassnacht M, Terzolo M, Allolio B, et al; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23):2189–97.CrossRefPubMedGoogle Scholar
  6. 6.
    Aubert S, Wacrenier A, Leroy X, et al. Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol. 2002;26(12):1612–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Cibas ES, Medeiros LJ, Weinberg DS, Gelb AB, Weiss LM. Cellular DNA profiles of benign and malignant adrenocortical tumors. Am J Surg Pathol. 1990;14(10):948–55.CrossRefPubMedGoogle Scholar
  8. 8.
    Morimoto R, Satoh F, Murakami O, et al. Immunohistochemistry of a proliferation marker Ki67/MIB1 in adrenocortical carcinomas: Ki67/MIB1 labeling index is a predictor for recurrence of adrenocortical carcinomas. Endocr J. 2008;55(1):49–55.CrossRefPubMedGoogle Scholar
  9. 9.
    Else T, Kim AC, Sabolch A, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282–326.CrossRefPubMedGoogle Scholar
  10. 10.
    Zou H, McGarry TJ, Bernal T, Kirschner MW. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science. 1999;285(5426):418–22.CrossRefPubMedGoogle Scholar
  11. 11.
    Tfelt-Hansen J, Kanuparthi D, Chattopadhyay N. The emerging role of pituitary tumor transforming gene in tumorigenesis. Clin Med Res. 2006;4(2):130–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Vlotides G, Eigler T, Melmed S. Pituitary tumor-transforming gene: physiology and implications for tumorigenesis. Endocr Rev. 2007;28(2):165–86.CrossRefPubMedGoogle Scholar
  13. 13.
    Haji Amousha MR, Sabet Kish N, Heshmat R, et al. Expression of the pituitary tumor transforming gene (PTTG1) in pheochromocytoma as a potential marker for distinguishing benign versus malignant tumors. Acta Med Iran. 2015;53(4):236–41.PubMedGoogle Scholar
  14. 14.
    Xu MD, Dong L, Qi P, et al. Pituitary tumor-transforming gene-1 serves as an independent prognostic biomarker for gastric cancer. Gastric Cancer. 2016;19(1):107–15.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhang J, Yang Y, Chen L, Zheng D, Ma J. Overexpression of pituitary tumor transforming gene (PTTG) is associated with tumor progression and poor prognosis in patients with esophageal squamous cell carcinoma. Acta Histochem. 2014;116(3):435–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Salehi F, Scheithauer BW, Sharma S, et al. Immunohistochemical expression of PTTG in brain tumors. Anticancer Res. 2013;33(1):119–22.PubMedGoogle Scholar
  17. 17.
    Demeure MJ, Coan KE, Grant CS, et al. PTTG1 overexpression in adrenocortical cancer is associated with poor survival and represents a potential therapeutic target. Surgery. 2013;154(6):1405–16; discussion 1416.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Lau SK, Weiss LM. The Weiss system for evaluating adrenocortical neoplasms: 25 years later. Hum Pathol. 2009;40(6):757–68.CrossRefPubMedGoogle Scholar
  19. 19.
    Kim TY, Jackson S, Xiong Y, et al. CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth. Proc Natl Acad Sci USA. 2013;110(42):16868–73.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Oncomine database. www.oncomine.org.
  21. 21.
    Giordano TJ, Kuick R, Else T, et al. Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin Cancer Res. 2009;15(2):668–76.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Pérez de Castro I, de Cárcer G, Malumbres M. A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy. Carcinogenesis. 2007;28(5):899–912.CrossRefGoogle Scholar
  23. 23.
    Cui W, Lu X, Zheng S, Ma Y, Liu X, Zhang W. The use of a combination of Ki-67, Galectin-3, and PTTG can distinguish the benign and malignant thyroid tumor. Clin Lab. 2012;58(5–6):419–26.PubMedGoogle Scholar
  24. 24.
    Duregon E, Rapa I, Votta A, et al. MicroRNA expression patterns in adrenocortical carcinoma variants and clinical pathologic correlations. Hum Pathol. 2014;45(8):1555–62.CrossRefPubMedGoogle Scholar
  25. 25.
    Karra H, Repo H, Ahonen I, et al. Cdc20 and securin overexpression predict short-term breast cancer survival. Br J Cancer. 2014;110(12):2905–13.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Yu SY, Liu HF, Wang SP, Chang CC, Tsai CM, Chao JI. Evidence of securin-mediated resistance to gefitinib-induced apoptosis in human cancer cells. Chem Biol Interact. 2013;203(2):412–22.CrossRefPubMedGoogle Scholar
  27. 27.
    Yu SH, Yang PM, Peng CW, Yu YC, Chiu SJ. Securin depletion sensitizes human colon cancer cells to fisetin-induced apoptosis. Cancer Lett. 2011 Jan 1;300(1):96–104.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2017

Authors and Affiliations

  • Minerva Angélica Romero Arenas
    • 1
  • Timothy G. Whitsett
    • 2
  • Anna Aronova
    • 3
  • Samuel A. Henderson
    • 1
  • Janine LoBello
    • 2
  • Mouhammed Amir Habra
    • 1
  • Elizabeth G. Grubbs
    • 1
  • Jeffrey E. Lee
    • 1
  • Kanishka Sircar
    • 1
  • Rasa Zarnegar
    • 3
  • Theresa Scognamiglio
    • 3
  • Thomas J. Fahey
    • 3
  • Nancy D. Perrier
    • 1
  • Michael J. Demeure
    • 2
  1. 1.The University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Translational Genomics Research InstitutePhoenixUSA
  3. 3.Weill Cornell Medical CollegeNew YorkUSA

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