Molecular genetic aspects of adrenocortical cancer

Adrenocortical cancer is a rare tumor originating from cortical adrenal cells, endowed with aggressive potential, a rapidly progressing course and an unfavorable prognosis. The complexity of early diagnosis of the disease is due to several factors: the variability of clinical manifestations associated with the initial multiregulatory influence of steroid hormones on the body’s homeostasis, the rare occurrence of the tumor and, as a result, the lack of understanding of the molecular mechanisms of its carcinogenesis.

The increased interest in recent years among oncologists and endocrinologists in understanding the fundamental and clinical aspects of adrenocortical cancer and the search for potential targets for new drugs has led to a detailed study of the cellular and molecular genetic mechanisms involved in normal adrenal ontogenesis and their role in tumor transformation. This review presents the currently known molecular genetic processes and their mediating auto-, para-, endocrine factors involved in normal adrenal ontogenesis and carcinogenesis. The paper analyzes results of trials published in international and Russian journals on molecular oncology and endocrinology indexed in the PubMed, CyberLeninka, Web of Science, Science Direct and eLIBRARY databases.

1. Else T., Kim A.C., Sabolch A. et al. Adrenocortical carcinoma. Endocrine Rev 2014;35(2):282–326. DOI: 10.1210/er.2013-1029

2. Pittaway J., Guasti L. Pathobiology and genetics of adrenocortical carcinoma. Mol Endocrinol 2020;62(2):105–19. DOI: 10.1530/JME-18-0122

3. Doghman M., Karpova T., Rodrigues G. et al. Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol Endocrinol 2007;21(12):2968–987. DOI: 10.1210/me.2007-01204

4. Bronswijk M.J.H., Laenen A., Bechter O.E. Clinical presentation, treatment modalities and outcome in patients with adrenocortical carcinoma: a single center experience. Neoplasma 2020;67(1): 209–3. DOI: 10.4149/neo_2019_190105N17

5. Ettaieb M., Kerkhofs T., van Engeland M., Haak H. Past, present and future of epigenetics in adrenocortical carcinoma. Cancers (Basel) 202013;12(5):1218. DOI: 10.3390/cancers12051218

6. Mizdrak M., Tičinović Kurir T., Božić J. The role of biomarkers in adrenocortical carcinoma: a review of current evidence and future perspectives. Biomedicines 2021;9(2):174. DOI: 10.3390/biomedicines9020174

7. Kronenberg H., Reed L., Polonsky K. et al. Williams textbook of Endocrinology. Moscow: GEOTAR-media, 2010. 208 p. (In Russ.).

8. Simon D.P., Hammer G.D. Adrenocortical stem and progenitor cells: implications for adrenocortical carcinoma. Mol Cell Endocrinol 2012;351(1):2–11. DOI: 10.1016/j.mce.2011.12.006

9. Walczak E.M., Hammer G.D. Regulation of the adrenocortical stem cell niche: implications for disease. Nat Rev Endocrinol 2015;11(1):14–28. DOI: 10.1016/j.mce.2011.12.006

10. Xing Y., Lerario A.M., Rainey W., Hammer G.D. Development of adrenal cortex zonation. Endocrinol Metab Clin North Am 2015;44(2):243–74. DOI: 10.1016/j.ecl.2015.02.001

11. Gummow B.M., Sheys J.O., Canselli V.R. et al. Reciprocal regulation of a glucocorticoid receptor-steroidogenic factor-1 transcription complex on the Dax-1 promoter by glucocorticoids and adrenocorticotropic hormone in the adrenal cortex. Mol Endocrinol 2006;20(11):2711–23. DOI: 10.1210/me.2005-0461

12. Gut P., Huber K., Lohr J. et al. Lack of an adrenal cortex in Sf1 mutant mice is compatible with the generation and differentiation of chromaffin cells. Development 2005;132(20):4611–9. DOI: 10.1242/dev.02052

13. Bland M., Fowkes R.C., Ingraham H.A. Differential requirement for steroidogenic factor-1 gene dosage in adrenal development versus endocrine function. Mol Endocrinol 2004;18(4):941–52. DOI: 10.1210/me.2003-0333

14. Walczak E.M., Kuick R., Finco I. et al. Wnt signaling inhibits adrenal steroidogenesis by cell-autonomous and non-cell-autonomous mechanisms. Mol Endocrinol 2014;28(9):1471–86. DOI: 10.1210/me.2014-1060

15. Isaeva A.V., Zima A.P., Shabalova I.P. et al. β-catenin: structure, function and role in malignant transformation of epithelial cells. Vestnik RAMN = Annals of the Russian Academy of Medical Sciences 2015;70(4):475–83. (In Russ.).

16. Hazell G., Horn G., Lightman S.L. et al. Dynamics of ACTH-mediated regulation of gene transcription in ATC1 and ATC7 adrenal zona fasciculata cell lines. Endocrinology 2019;160(3):587–604. DOI: 10.1210/en.2018-00840

17. Pitsava G., Maria A.G., Faucz F.R. Disorders of the adrenal cortex: genetic and molecular aspects. Front Endocrinol (Lausanne) 2022;13:931389. DOI: 10.3389/fendo.2022.931389

18. Belogorsky A., Baquedano M.S., Guercio G. et al. Adrenarche: postnatal adrenal zonation and hormonal and metabolic regulation. Horm Res 2008;70:257–67. DOI: 10.1159/000157871

19. King P., Paul A., Laufer E. SHH signaling regulates adrenocortical development and identifies progenitors of steroidogenic lineages. Proc Natl Acad Sci USA 2009;106(50):21185–90. DOI: 10.1073/pnas.0909471106

20. Finco I., Lerario A.M., Hammer G.D. Sonic hedgehog and WNT signaling promote adrenal gland regeration in male mice. Endocrinology 2018;159(2):579–96. DOI: 10.1210/en.2017-03061

21. Gummow B.M., Scheys J.O., Cancelli V.R. et al. Reciprocal regulation of a glucocorticoid receptor-steroidogenic factor-1 transcription complex on the Dax-1 promoter by glucocorticoids and adrenocorticotropic hormone in the adrenal cortex. Mol Endocrinol 2006;20(11):2711–23. DOI: 10.1210/me.2005-0461

22. Abou Nader N., Zamberlam G., Boyer A. Transgenic mouse models to study the development and maintenance of the adrenal cortex. Int J Mol Sci 2022;23(22):14388. DOI: 10.3390/ijms232214388

23. Maity P., Mondal A., Das R. et al. Diagnostic and prognostic utility of SF-1 in adrenal cortical tumours. Indian J Pathol Microbiol 2022;65(4):814–20. DOI: 10.4103/ijpm.ijpm_153_21

24. Muzzi J.C.D., Magno J.M., Souza J.S. et al. Comprehensive characterization of the regulatory landscape of adrenocortical carcinoma: novel transcription factors and targets associated with prognosis. Cancers (Basel) 2022;14(21):5279. DOI: 10.3390/cancers14215279

25. Tkachuk A.V., Beltsevich D.G., Porubayeva E.E., Urusova L.S. Morphological predictors of the efficacy of mitotane therapy in adrenocortical cancer. Problemy endokrinologii = Problems of Endocrinology 2023;68(6):76–88. (In Russ.). DOI: 10.14341/probl13172

26. Cherepanov S.A., Baklaushev V.P., Gabashvilli A.N. et al. Hedgehog signaling in the pathogenesis of neuro-oncology diseases. Biomeditsinskaya khimiya = Biomedical Chemistry 2015;61(3):332–42. (In Russ.).

27. Byakhova M.M., Voronkova I.A., Krivosheev A.B. Molecular and genetic characteristics of adrenocortical cancer. Russkij medicinskij zhurnal = Russian Medical Journal 2017;22:1651–3. (In Russ.).

28. Gennadinik A.G., Nelaeva A.A. Role insulin-like growth factor-I in metabolism, regulation of cellular renewal and aging processe. Ozhirenie i metabolizm = Obesity and metabolism 2010;2:10–6. (In Russ.).

29. Kostyleva O.I., Gershteyn E.S., Yermilova V.D. et al. Insulin-like growth factor in blood serum of breast cancer patients. Vestnik TGU = TGU Bulletin 2014;19(1):16–20. (In Russ.).

30. Shevchenko V.E., Bryukhovetskiy I.S., Nikiforova Z.N. et al. The transforming growth factor beta-1 in the oncogenesis of human lung adenocarcinoma. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2017;4(4):67–74. DOI: 10.17650/2313-805X-2017-4-3-67-74 (In Russ.).

31. Neel J.Ch., Humbert L., Lebrun J.J. et al. The dual role of TGF β in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol 2012;2012:381428. DOI: 10.5402/2012/381428

32. Pereira S.S., Oliveira S., Monteiro M.P., Pignatelli D. Angiogenesis in the normal adrenal fetal cortex and adrenocortical tumors. Cancers (Basel) 2021;13(5):1030. DOI: 10.3390/cancers1305103

33. Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer 2011;2(12):1097–105. DOI: 10.1177/1947601911423031

34. Liggins G.C. Adrenocortical-related maturational events in the fetus. Am J Obstet Gynecol 1976;126(7):93141. DOI: 10.1016/0002-9378(76)90680-3

35. Kolomecki K., Stepien H., Bartos M., Kuzdak K. Usefulness of VEGF, MMP-2, MMP-3 and TIMP-2 serum level evaluation in patients with adrenal tumours. Endocr Regul 2001;35(1):9–16.

36. Zacharieva S., Atanassova I., Orbetzova M. et al. Circulating vascular endothelial growth factor and active renin concentrations and prostaglandin E2 urinary excretion in patients with adrenal tumours. Eur J Endocrinol 2004;150(3):345–9. DOI: 10.1530/eje.0.1500345

37. Bernini G.P., Moretti A., Bonadio A.G. et al. Angiogenesis in human normal and pathologic adrenal cortex. J Clin Endocrinol Metab 2002;87(11):4961–5. DOI: 10.1210/jc.2001-011799

38. Kroiss M., Reuss M., Kühner D. et al. Sunitinib inhibits cell proliferation and alters steroidogenesis by down-regulation of HSD3B2 in adrenocortical carcinoma cells. Front Endocrinol (Lausanne) 2011;2:27. DOI: 10.3389/fendo.2011.00027

39. De Fraipont F., El Atifi M., Gicquel C. et al. Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations. J Clin Endocrinol Metab 2000;85(12): 4734–41. DOI: 10.1210/jcem.85.12.7012

40. Xu Y.Z., Zhu Y., Shen Z.J. et al. Significance of heparanase-1 and vascular endothelial growth factor in adrenocortical carcinoma angiogenesis: potential for therapy. Endocrine 2011;40(3):445–51. DOI: 10.1007/s12020-011-9502-1

41. Pozdeyev N., Fishbein L., Gay L.M. et al. Targeted genomic analysis of 364 adrenocortical carcinomas. Endocr Relat Cancer 2021;28(10):671–81. DOI: 10.1530/ERC-21-0040

42. Silvestri E., Lombardi A., De Lange P. et al. Studies of complex biological systems with applications in molecular medicine: the need for integration of transcriptomic and proteomic approaches. J Biomed Biotechnol 2011;2011:810242.

43. Detomas M., Pivonello C., Pellegrini B. et al. MicroRNAs and long non-coding RNAs in adrenocortical carcinoma. Cells 2022;11(14):2234. DOI: 10.3390/cells11142234

44. Decmann A., Perge P., Turai P.I. et al. Non-coding RNAs in adrenocortical cancer: from pathogenesis to diagnosis. Cancers 2020;12(2):461. DOI: 10.3390/cancers12020461

45. Koperski Ł., Kotlarek M., Świerniak M. et al. Next-generation sequencing reveals microRNA markers of adrenocortical tumors malignancy. Oncotarget 2017;8(30):49191–200.

46. Kwok G.T.Y., Zhao J.T., Glover A.R. et al. microRNA-431 as a chemosensitizer and potentiator of drug activity in adreno-cortical сarcinoma. Oncologist 2019;24(6):e241–50. DOI: 10.1634/theoncologist.2018-0849

47. Wang S., Li M.Y., Liu Y. et al. The role of microRNA in cisplatin resistance or sensitivity. Expert Opin Ther Targets 2020;24:885–97. DOI: 10.1080/14728222.2020.1785431

48. Turai P.I., Herold Z., Nyirő G. et al. Tissue miRNA combinations for the differential diagnosis of adrenocortical carcinoma and adenoma established by artificial intelligence. Cancers (Basel) 2022;14(4):895. DOI: 10.3390/cancers14040895

49. Ye B., Shi J., Kang H. et al. Advancing pan-cancer gene expression survial analysis by inclusion of non-coding RNA. RNA Biol 2020;17(11):1666–73. DOI: 10.1080/15476286.2019

50. Darabi S., Braxton D.R., Eisenberg B.L., Demeure M.J. Molecular genomic profiling of adrenocortical cancers in clinical practice. Surgery 2021;169(1):138–44. DOI: 10.1016/j.surg.2020.05.039

51. Arlt W., Biehl M., Taylor A.E. et al. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. J Clin Endocrinol Metab 2011;96(12):3775–84. DOI: 10.1210/jc.2011-1565

52. Uchida T., Nishimoto K., Fukumura Y. et al. Disorganized steroidogenesis in adrenocortical carcinoma, a case study. Endocr Pathol 2017;28(1):27–35. DOI: 10.1007/s12022-016-9441-8

53. Sasano H., Miyazaki S., Sawai T. et al. Primary pigmented nodular adrenocortical disease (PPNAD): immunohistochemical and in situ hybridization analysis of steroidogenic enzymes in eight cases. Mod Pathol 1992;5(1):23–9.

54. Hou Y., Gao Y., Guo S. et al. Applications of spatially resolved omics in the field of endocrine tumors. Front Endocrinol (Lausanne) 2023;13:993081. DOI: 10.3389/fendo.2022.993081

55. Bothou C., Penton D., Abate A. et al. A comprehensive investigation of steroidogenic signaling in classical and new experimental cell models of adrenocortical carcinoma. Cells 2022;11(9):1439. DOI: 10.3390/cells11091439

56. Kerkhofs T.M., Kerstens M.N., Kema I.P. et al. Diagnostic value of urinary steroid profiling in the evaluation of adrenal tumors. Horm Cancer 2015;6(4):168–75. DOI: 10.1007/s12672-015-0224-3

57. Shafigullina Z.R., Velikanova L.I., Vorohobina N.V. et al. The diagnostical importance of steroid profiles of biological fluids of patients with Cushing’s syndrome. Problemy endokrinologii = Problems of Endocrinology 2015;61(4):4–8. (In Russ.). DOI: 10.14341/probl20156144-8

58. Velikanova L.I., Shafigullina Z.R., Lisitsin A.A. et al. Different types of urinary steroid profiling obtained by high-performance liquid chromatography and gas chromatography-mass spectrometry in patients with adrenocortical carcinoma. Horm Cancer 2016;7(56):327–35. DOI: 10.1007/s12672-016-0267-0

59. Schweitzer S., Kunz M., Kurlbaum M. et al. Plasma steroid metabolome profiling for the diagnosis of adrenocortical carcinoma. Eur J Endocrinol 2019;180(2):117–25. DOI: 10.1530/EJE-18-0782

60. Bancos I., Taylor A.E., Chortis V. et al. Urinary steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT trial: a prospective validation study. Lancet Diabetes Endocrinol 2020;8:773–81. DOI: 10.1016/S2213-8587(20)30218-7

61. Paragliola R.M., Corsello A., Locantore P. et al. Medical approaches in adrenocortical carcinoma. Biomedicines 2020;8(12):551. DOI: 10.3390/biomedicines8120551

62. Lam A.K. Adrenocortical carcinoma: updates of clinical and pathological features after renewed World Health Organisation classification and pathology staging. Biomedicines 2021;9(2):175. DOI: 10.3390/biomedicines9020175

63. Terzolo M., Fassnacht M., Perotti P. et al. Results of the ADIUVO study, the first randomized trial on adjuvant mitotane in adrenocortical carcinoma patients. J Endoc Soc 2021;5(Suppl. 1): A166–7. DOI: 10.1210/jendso/bvab048.336

64. Haluska P., Worden F., Olmos D. et al. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol 2010;65:765–73. DOI: 10.1007/s00280-009-1083-9

65. Lerario A.M., Worden F.P., Ramm C.A. et al. The combination of insulin-like growth factor receptor 1 (IGF1R) antibody cixutumumab and mitotane as a first-line therapy for patients with recurrent/metastatic adrenocortical carcinoma: a multi-institutional nci-sponsored trial. Horm Cancer 2014;5:232–9. DOI: 10.1007/s12672-014-0182-1

66. Fassnacht M., Berruti A., Baudin E. et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol 2015;16(4):426–35. DOI: 10.1016/S1470-2045(15)70081-1

67. Kroiss M., Quinkler M. et al. Sunitinib in refractory adrenocortical carcinoma: a phase ii, single-arm, open-label trial. J Clin Endocrinol Metab 2012;97(10):3495–503. DOI: 10.1210/jc.2012-1419

68. Berruti A., Sperone P., Ferrero A. et al. Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. Eur J Endocrinol 2012;166(3): 451–8. DOI: 10.1530/EJE-11-0918

69. Bedrose S., Miller K.C., Altameemi L. et al. Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma. J Immunother Cancer 2020;8:e001009. DOI: 10.1136/jitc-2020-001009

70. Kroiss M., Megerle F., Kurlbaum M. et al. Objective response and prolonged disease control of advanced adrenocortical carcinoma with cabozantinib. J Clin Endocrinol Metab 2020;105(5):14618. DOI: 10.1210/clinem/dgz318

71. O’Sullivan C., Edgerly M., Velarde M. et al. The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer. J Clin Endocrinol Metab 2014;99(4):1291–7. DOI: 10.1210/jc.2013-2298

72. Kroiss M., Deutschbein T., Schlötelburg W. et al. Treatment of refractory adrenocortical carcinoma with thalidomide: analysis of 27 patients from the European Network for the Study of Adrenal Tumours Registry. Exp Clin Endocrinol Diabetes 2019;127(9): 578–84. DOI: 10.1055/a-0747-5571

73. Wortmann S., Quinkler M., Ritter C. et al. Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. Eur J Endocrinol 2010;162(2):349–56. DOI: 10.1530/EJE-09-0804

74. Laganà M., Grisanti S., Ambrosini R. et al. Phase II study of cabazitaxel as second-third line treatment in patients with metastatic adrenocortical carcinoma. ESMO Open 2022;7(2):100422. DOI: 10.1016/j.esmoop.2022.100422

75. Berruti A., Sperone P., Bellini E. et al. Metronomic therapy concepts in the management of adrenocortical carcinoma. Horm Cancer 2011;2(6):378–84. DOI: 10.1007/s12672-011-0087-1

76. Uchihara M., Tanioka M., Kojima Y. et al. Clinical management and outcomes associated with etoposide, doxorubicin, and cisplatin plus mitotane treatment in metastatic adrenocortical carcinoma: a single institute experience. Int J Clin Oncol 2021;26(12):2275–81. DOI: 10.1007/s10147-021-02021-8

77. Carneiro B.A., Konda B., Costa R.B. et al. Nivolumab in metastatic adrenocortical carcinoma: results of a phase 2 trial. J Clin Endocrinol Metab 2019;104:6193–200. DOI: 10.1210/jc.2019-00600

78. Le Tourneau C., Hoimes C., Zarwan C. et al. Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the javelin solid tumor trial. J Immunother Cancer 2018;6(1):111. DOI: 10.1186/s40425-018-0424-9

79. Alyateem G., Nilubol N. Current status and future targeted therapy in adrenocortical cancer. Front Endocrinol (Lausanne) 2021;12:613248. DOI: 10.3389/fendo.2021.613248