Prognostic value of the expression of carbonic anhydrase 9 in combination with other markers in patients with clear cell renal cell carcinoma

Background. The proportion of renal cell carcinoma (RCC) in the structure of oncological incidence in Russia is 3.9 %. This nosology has a leading position by the growth rate. The number of new cases of RCC from 2004 to 2014 increased by 42.9 %. Carbonic anhydrase (CA) enzymes are transmembrane enzymes that play an important role in pH regulation catalyzing reversible reactions of carbonic acid to carbon dioxide and water. Recently we have seen studies on prognostic and predictive value of CA9 expression in clear cell RCC.

Objective – reveal relationship between CA9 expression and proliferative activity, apoptosis, morphological picture and clinical course of a tumor.

Materials and methods. The study included 67 patients (47 men and 20 women) aged from 32 to 73 years (55.0 ± 7.6 years), suffering from clear cell RCC. All the patients were treated at the Medical Radiological Research Center. Follow-up period lasted from 8 to 116 months (mean – 36.5 months). Patients underwent nephrectomy, histological study with Fuhrman nuclear grading, immunohistochemistry with antibodies against p53, bcl-2, Ki-67 and CA9.

Results and conclusions. CA9 expression is associated with the expression of bcl-2, while the lack of CA9 expression is associated with p53. Loss of CA9 expression is a poor prognostic factor and it is associated with the development of metastasis and recurrence of the disease, as well as lower disease-free survival. 

1. Каприн А.Д., Старинский В.В., Петрова Г.В. Злокачественные новообразования в России в 2014 году. Москва, 2016г.

2. Takacova M1, Bartosova M, Skvarkova L, Zatovicova M, Vidlickova I, Csaderova L, Barathova M, Breza J Jr, Bujdak P, Pastorek J, Breza J Sr, Pastorekova S. Carbonic anhydrase IX is a clinically significant tissue and serum biomarker associated with renal cell carcinoma. Oncol Lett. 2013 Jan;5(1):191-197. Epub 2012 Oct 26.

3. Oosterwijk E, Ruiter DJ, Hoedemaeker PJ, Pauwels EK, Jonas U, Zwartendijk J, Warnaar SO.Monoclonal antibody G 250 recognizes a determinant present in renal-cell carcinoma and absent from normal kidney. Int J Cancer. 1986 Oct 15;38(4):489-94.

4. Jeannette C. Oosterwijk-Wakka, Otto C. Boerman, Peter F. A. Mulders, Egbert Oosterwijk. Application of Monoclonal Antibody G250 Recognizing Carbonic Anhydrase IX in Renal Cell Carcinoma. Int J Mol Sci. 2013 June; 14(6): 11402–11423. Published online 2013 May 29.

5. Stillebroer AB, Mulders PF, Boerman OC, Oyen WJ, Oosterwijk E. Carbonic anhydrase IX in renal cell carcinoma: implications for prognosis, diagnosis, and therapy. Eur Urol. 2010 Jul;58(1):75-83. doi: 10.1016/j.eururo.2010.03.015. Epub 2010 Mar 23. Review.

6. Leibovich BC, Sheinin Y, Lohse CM, Thompson RH, Cheville JC, Zavada J, Kwon ED. Carbonic anhydrase IX is not an independent predictor of outcome for patients with clear cell renal cell carcinoma. J Clin Oncol. 2007 Oct 20;25(30):4757-64.

7. Muriel López C, Esteban E, Berros JP, Pardo P, Astudillo A, Izquierdo M, Crespo G, Sanmamed M, Fonseca PJ, Martínez-Camblor P. Prognostic factors in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2012 Dec;10(4):262-70. doi: 10.1016/j.clgc.2012.06.005. Epub 2012 Sep 7.

8. Muriel López C, Esteban E, Astudillo A, Pardo P, Berros JP, Izquierdo M, Crespo G, Fonseca PJ, Sanmamed M, Martínez-Camblor P. Predictive factors for response to treatment in patients with advanced renal cell carcinoma. Invest New Drugs. 2012 Dec;30(6):2443-9. doi: 10.1007/s10637-012-9836-4. Epub 2012 May 27.

9. Zhang BY, Thompson RH, Lohse CM, Dronca RS, Cheville JC, Kwon ED, Leibovich BC. Carbonic anhydrase IX (CAIX) is not an independent predictor of outcome in patients with clear cell renal cell carcinoma (ccRCC) after long-term follow-up. BJU Int. 2013 Jun;111(7):1046-53. doi: 10.1111/bju.12075. Epub 2013 Apr 2.

10. Tostain J, Li G, Gentil-Perret A, Gigante M. Carbonic anhydrase 9 in clear cell renal cell carcinoma: a marker for diagnosis, prognosis and treatment. Eur J Cancer. 2010 Dec;46(18):3141-8. doi: 10.1016/j.ejca.2010.07.020. Epub 2010 Aug 13. Review.

11. Горбань Н.А., Иванова С.В., Карякин О.Б., Попов А.М., Варламов С.А., Ганов Д.И. Клиническое значение маркеров пролиферации и апоптоза в светлоклеточном варианте почечно-клеточного рака. Онкоурология,1, 2014, с 30-35.

12. World Health Organization Classification of Tumours. Pathology & Genetics: Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press, 2004.

13. Elizabeth M. Genega, Musie Ghebremichael, Robert Najarian, Yineng Fu, Yihong Wang, Pedram Argani, Chiara Grisanzio, Sabina Signoretti. Carbonic Anhydrase IX Expression in Renal Neoplasms: Correlation with Tumor Type and Grade. Am J Clin Pathol. Author manuscript; available in PMC 2013 September 20. Published in final edited form as: Am J Clin Pathol. 2010 December; 134(6): 873–879.

14. Amanda Mickley, Olga Kovaleva, Julia Kzhyshkowska, Alexei Gratchev. Molecular and immunologic markers of kidney cancer—potential applications in predictive, preventive and personalized medicine. EPMA J. 2015; 6: 20. Published online 2015 October 20. doi: 10.1186/s13167-015-0042-2

15. Uzunlar AK, Sahin H, Yilmaz F, Ozekinci S Expression of p53 oncoprotein and bcl-2 in renal cell carcinoma. Saudi Med J. 2005 Jan;26(1):37-41.

16. Warburton HE, Brady M, Vlatković N, Linehan WM, Parsons K, Boyd MT. p53 regulation and function in renal cell carcinoma. Cancer Res. 2005 Aug 1;65(15):6498-503.

17. Chamie K, Klöpfer P, Bevan P, Störkel S, Said J, Fall B, Belldegrun AS, Pantuck AJ. Carbonic anhydrase-IX score is a novel biomarker that predicts recurrence and survival for high-risk, nonmetastatic renal cell carcinoma: Data from the phase III ARISER clinical trial. Urol Oncol. 2015 May;33(5):204.e25-33.

18. Bui MH, Visapaa H, Seligson D, Kim H, Han KR, Huang Y, Horvath S, Stanbridge EJ, Palotie A, Figlin RA, Belldegrun AS. Prognostic value of carbonic anhydrase IX and KI67 as predictors of survival for renal clear cell carcinoma. J Urol. 2004 Jun;171(6 Pt 1):2461-6.

19. Pan Z, Grizzle W, Hameed O. Significant variation of immunohistochemical marker expression in paired primary and metastatic clear cell renal cell carcinomas. Am J Clin Pathol. 2013 Sep;140(3):410-8.

20. Zhao Z, Liao G, Li Y, Zhou S, Zou H, Fernando S. Prognostic value of carbonic anhydrase IX immunohistochemical expression in renal cell carcinoma: a meta-analysis of the literature. PLoS One. 2014 Nov 26;9(11):e114096.

21. Choueiri TK, Cheng S, Qu AQ, Pastorek J, Atkins MB, Signoretti S. Carbonic anhydrase IX as a potential biomarker of efficacy in metastatic clear-cell renal cell carcinoma patients receiving sorafenib or placebo: analysis from the treatment approaches in renal cancer global evaluation trial (TARGET). Urol Oncol. 2013 Nov;31(8):1788-93. doi: 10.1016/j.urolonc.2012.07.004. Epub 2012 Nov 7.