Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Advances in translational research of the rare cancer type adrenocortical carcinoma

Nature Reviews Cancer volume 23, pages 805–824 (2023)Cite this article

Subjects

Abstract

Adrenocortical carcinoma is a rare malignancy with an annual worldwide incidence of 1–2 cases per 1 million and a 5-year survival rate of <60%. Although adrenocortical carcinoma is rare, such rare cancers account for approximately one third of patients diagnosed with cancer annually. In the past decade, there have been considerable advances in understanding the molecular basis of adrenocortical carcinoma. The genetic events associated with adrenocortical carcinoma in adults are distinct from those of paediatric cases, which are often associated with germline or somatic TP53 mutations and have a better prognosis. In adult primary adrenocortical carcinoma, the main somatic genetic alterations occur in genes that encode proteins involved in the WNT–β-catenin pathway, cell cycle and p53 apoptosis pathway, chromatin remodelling and telomere maintenance pathway, cAMP–protein kinase A (PKA) pathway or DNA transcription and RNA translation pathways. Recently, integrated molecular studies of adrenocortical carcinomas, which have characterized somatic mutations and the methylome as well as gene and microRNA expression profiles, have led to a molecular classification of these tumours that can predict prognosis and have helped to identify new therapeutic targets. In this Review, we summarize these recent translational research advances in adrenocortical carcinoma, which it is hoped could lead to improved patient diagnosis, treatment and outcome.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Dysregulated molecular pathways in paediatric and adult adrenocortical carcinoma.
Fig. 2: Dysregulated molecular pathways owing to epigenomic changes in adult adrenocortical carcinoma.
Fig. 3: Steroidogenesis pathway of the adrenal cortex and its dysregulation in adrenocortical carcinoma.

Similar content being viewed by others

References

  1. Bilimoria, K. Y. et al. Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors. Cancer 113, 3130–3136 (2008).

    PubMed  Google Scholar 

  2. Else, T. et al. Adrenocortical carcinoma. Endocr. Rev. 35, 282–326 (2014).

    CAS  PubMed  Google Scholar 

  3. Kebebew, E., Reiff, E., Duh, Q. Y., Clark, O. H. & McMillan, A. Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J. Surg. 30, 872–878 (2006).

    PubMed  Google Scholar 

  4. Tella, S. H., Kommalapati, A., Yaturu, S. & Kebebew, E. Predictors of survival in adrenocortical carcinoma: an analysis from the national cancer database. J. Clin. Endocrinol. Metab. 103, 3566–3573 (2018).

    PubMed  Google Scholar 

  5. Tierney, J. F. et al. National treatment practice for adrenocortical carcinoma: have they changed and have we made any progress? J. Clin. Endocrinol. Metab. 104, 5948–5956 (2019).

    PubMed  Google Scholar 

  6. Kerkhofs, T. M. et al. Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993. Eur. J. Cancer 49, 2579–2586 (2013).

    PubMed  Google Scholar 

  7. McAteer, J. P., Huaco, J. A. & Gow, K. W. Predictors of survival in pediatric adrenocortical carcinoma: a Surveillance, Epidemiology, and End Results (SEER) program study. J. Pediatr. Surg. 48, 1025–1031 (2013).

    PubMed  Google Scholar 

  8. Fassnacht, M. et al. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a revised TNM classification. Cancer 115, 243–250 (2009).

    PubMed  Google Scholar 

  9. Elhassan, Y. S. et al. S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study. Eur. J. Endocrinol. 186, 25–36 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Beuschlein, F. et al. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J. Clin. Endocrinol. Metab. 100, 841–849 (2015).

    CAS  PubMed  Google Scholar 

  11. Michalkiewicz, E. et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J. Clin. Oncol. 22, 838–845 (2004).

    CAS  PubMed  Google Scholar 

  12. Loncar, Z. et al. Survival and prognostic factors for adrenocortical carcinoma: a single institution experience. BMC Urol. 15, 43 (2015).

    PubMed  PubMed Central  Google Scholar 

  13. Li, P., Su, X., Zhang, X., Sun, L. & Zhang, G. Prognostic factors of adrenocortical carcinoma: experience from a Regional Medical Center in Eastern China. Int. J. Gen. Med. 16, 453–465 (2023).

    PubMed  PubMed Central  Google Scholar 

  14. Lughezzani, G. et al. The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the International Union Against Cancer-staging system: a North American validation. Eur. J. Cancer 46, 713–719 (2010).

    PubMed  Google Scholar 

  15. Terzolo, M. et al. Results of the ADIUVO study, the first randomized trial on adjuvant mitotane in adrenocortical carcinoma patients. J. Endocr. Soc. 5, A166–A167 (2021).

    PubMed Central  Google Scholar 

  16. Fassnacht, M. et al. Combination chemotherapy in advanced adrenocortical carcinoma. N. Engl. J. Med. 366, 2189–2197 (2012).

    CAS  PubMed  Google Scholar 

  17. Fassnacht, M. et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur. J. Endocrinol. 179, G1–G46 (2018).

    CAS  PubMed  Google Scholar 

  18. Challis, B. G. et al. Familial adrenocortical carcinoma in association with Lynch syndrome. J. Clin. Endocrinol. Metab. 101, 2269–2272 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Gatta-Cherifi, B. et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d’Etude des Tumeurs Endocrines database. Eur. J. Endocrinol. 166, 269–279 (2012).

    CAS  PubMed  Google Scholar 

  20. Hampel, H. et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N. Engl. J. Med. 352, 1851–1860 (2005).

    CAS  PubMed  Google Scholar 

  21. Herrmann, L. J. et al. TP53 germline mutations in adult patients with adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 97, E476–E485 (2012).

    CAS  PubMed  Google Scholar 

  22. MacFarland, S. P. et al. Management of adrenal masses in patients with Beckwith–Wiedemann syndrome. Pediatr. Blood Cancer 64, 10.1002/pbc.26432 (2017).

    PubMed Central  Google Scholar 

  23. Pinto, E. M. et al. Identification of clinical and biologic correlates associated with outcome in children with adrenocortical tumors without germline TP53 mutations: a st jude adrenocortical tumor registry and children’s oncology group study. J. Clin. Oncol. 35, 3956–3963 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Raymond, V. M. et al. Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 98, E119–E125 (2013).

    CAS  PubMed  Google Scholar 

  25. Raymond, V. M. et al. Adrenocortical carcinoma is a Lynch syndrome-associated cancer. J. Clin. Oncol. 31, 3012–3018 (2013).

    PubMed  PubMed Central  Google Scholar 

  26. Seki, M. et al. Loss of normal allele of the APC gene in an adrenocortical carcinoma from a patient with familial adenomatous polyposis. Hum. Genet. 89, 298–300 (1992).

    CAS  PubMed  Google Scholar 

  27. Shiroky, J. S., Lerner-Ellis, J. P., Govindarajan, A., Urbach, D. R. & Devon, K. M. Characteristics of adrenal masses in familial adenomatous polyposis. Dis. Colon Rectum 61, 679–685 (2018).

    PubMed  Google Scholar 

  28. Wakatsuki, S. et al. Adrenocortical tumor in a patient with familial adenomatous polyposis: a case associated with a complete inactivating mutation of the APC gene and unusual histological features. Hum. Pathol. 29, 302–306 (1998).

    CAS  PubMed  Google Scholar 

  29. Wasserman, J. D. et al. Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a Children’s Oncology Group study. J. Clin. Oncol. 33, 602–609 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Juhlin, C. C. et al. What did we learn from the molecular biology of adrenal cortical neoplasia? From histopathology to translational genomics. Endocr. Pathol. 32, 102–133 (2021).

    CAS  PubMed  Google Scholar 

  31. Grisanti, S., Cosentini, D., Sigala, S. & Berruti, A. Molecular genotyping of adrenocortical carcinoma: a systematic analysis of published literature 2019–2021. Curr. Opin. Oncol. 34, 19–28 (2022).

    CAS  PubMed  Google Scholar 

  32. Else, T. et al. Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series. Eur. J. Endocrinol. 177, 439–444 (2017).

    CAS  PubMed  Google Scholar 

  33. Grisanti, S. et al. 29MO Germline variants NGS characterization in patients with non-syndromic adrenocortical carcinoma. ESMO Open 8, 101050 (2023).

    Google Scholar 

  34. Custodio, G. et al. Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. J. Clin. Oncol. 31, 2619–2626 (2013).

    PubMed  PubMed Central  Google Scholar 

  35. Latronico, A. C. et al. An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors. J. Clin. Endocrinol. Metab. 86, 4970–4973 (2001).

    CAS  PubMed  Google Scholar 

  36. Pinto, E. M. et al. Founder effect for the highly prevalent R337H mutation of tumor suppressor p53 in Brazilian patients with adrenocortical tumors. Arq. Bras. Endocrinol. Metab. 48, 647–650 (2004).

    Google Scholar 

  37. Ribeiro, R. C. et al. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc. Natl Acad. Sci. USA 98, 9330–9335 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Mete, O. et al. Overview of the 2022 who classification of adrenal cortical tumors. Endocr. Pathol. 33, 155–196 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Minner, S., Schreiner, J. & Saeger, W. Adrenal cancer: relevance of different grading systems and subtypes. Clin. Transl. Oncol. 23, 1350–1357 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Weiss, L. M. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am. J. Surg. Pathol. 8, 163–169 (1984).

    CAS  PubMed  Google Scholar 

  41. Weiss, L. M., Medeiros, L. J. & Vickery, A. L. Jr Pathologic features of prognostic significance in adrenocortical carcinoma. Am. J. Surg. Pathol. 13, 202–206 (1989).

    CAS  PubMed  Google Scholar 

  42. Pittaway, J. F. H. & Guasti, L. Pathobiology and genetics of adrenocortical carcinoma. J. Mol. Endocrinol. 62, R105–R119 (2019).

    CAS  PubMed  Google Scholar 

  43. Assie, G. et al. Integrated genomic characterization of adrenocortical carcinoma. Nat. Genet. 46, 607–612 (2014). This study demonstrates that cataloguing the genomic changes in adrenocortical carcinoma reveals distinct molecular groups and that these are associated with prognosis.

    CAS  PubMed  Google Scholar 

  44. Zheng, S. et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 29, 723–736 (2016). This study comprehensively identifies genomic alterations associated with adult adrenocortical carcinoma and their association with patient outcome.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sbiera, I. et al. Role of FGF receptors and their pathways in adrenocortical tumors and possible therapeutic implications. Front. Endocrinol. 12, 795116 (2021).

    Google Scholar 

  46. Tamburello, M. et al. FGF/FGFR signaling in adrenocortical development and tumorigenesis: novel potential therapeutic targets in adrenocortical carcinoma. Endocrine 77, 411–418 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Pereira, S. S. et al. IGF2 role in adrenocortical carcinoma biology. Endocrine 66, 326–337 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Pinto, E. M. et al. Genomic landscape of paediatric adrenocortical tumours. Nat. Commun. 6, 6302 (2015). This study shows the genomic alterations that are prevalent in and unique to paediatric adrenocortical carcinomas.

    CAS  PubMed  Google Scholar 

  49. Pozdeyev, N. et al. Targeted genomic analysis of 364 adrenocortical carcinomas. Endocr. Relat. Cancer 28, 671–681 (2021). This study is one of the largest mutational analyses performed using NGS and identifies novel genomic alterations that could be targeted for therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Hoadley, K. A. et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173, 291–304.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Knijnenburg, T. A. et al. Genomic and molecular landscape of DNA damage repair deficiency across the cancer genome atlas. Cell Rep. 23, 239–254.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sondka, Z. et al. The COSMIC cancer gene census: describing genetic dysfunction across all human cancers. Nat. Rev. Cancer 18, 696–705 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kurtz, A. et al. Somatic mitochondrial DNA mutations in neurofibromatosis type 1-associated tumors. Mol. Cancer Res. 2, 433–441 (2004).

    CAS  PubMed  Google Scholar 

  54. Wang, Q. et al. Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Hum. Genet. 112, 117–123 (2003).

    CAS  PubMed  Google Scholar 

  55. Santos, M. A. et al. DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier. Nature 514, 107–111 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Pemov, A., Park, C., Reilly, K. M. & Stewart, D. R. Evidence of perturbations of cell cycle and DNA repair pathways as a consequence of human and murine NF1-haploinsufficiency. BMC Genomics 11, 194 (2010).

    PubMed  PubMed Central  Google Scholar 

  57. Bielski, C. M. et al. Genome doubling shapes the evolution and prognosis of advanced cancers. Nat. Genet. 50, 1189–1195 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Letouze, E. et al. SNP array profiling of childhood adrenocortical tumors reveals distinct pathways of tumorigenesis and highlights candidate driver genes. J. Clin. Endocrinol. Metab. 97, E1284–E1293 (2012).

    CAS  PubMed  Google Scholar 

  59. Zack, T. I. et al. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45, 1134–1140 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Juhlin, C. C. et al. Whole-exome sequencing characterizes the landscape of somatic mutations and copy number alterations in adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 100, E493–E502 (2015).

    CAS  PubMed  Google Scholar 

  61. Gicquel, C. et al. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors. J. Clin. Endocrinol. Metab. 78, 1444–1453 (1994).

    CAS  PubMed  Google Scholar 

  62. Gicquel, C. et al. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors. J. Clin. Endocrinol. Metab. 82, 2559–2565 (1997).

    CAS  PubMed  Google Scholar 

  63. Peixoto Lira, R. C. et al. IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis. Endocr. Relat. Cancer 23, 481–493 (2016).

    PubMed  Google Scholar 

  64. Guillaud-Bataille, M. et al. IGF2 promotes growth of adrenocortical carcinoma cells, but its overexpression does not modify phenotypic and molecular features of adrenocortical carcinoma. PLoS ONE 9, e103744 (2014).

    PubMed  PubMed Central  Google Scholar 

  65. Nielsen, H. M. et al. Copy number variations alter methylation and parallel IGF2 overexpression in adrenal tumors. Endocr. Relat. Cancer 22, 953–967 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Rosati, R. et al. High frequency of loss of heterozygosity at 11p15 and IGF2 overexpression are not related to clinical outcome in childhood adrenocortical tumors positive for the R337H TP53 mutation. Cancer Genet. Cytogenet. 186, 19–24 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Szabo, P. E., Tang, S. H., Silva, F. J., Tsark, W. M. & Mann, J. R. Role of CTCF binding sites in the Igf2/H19 imprinting control region. Mol. Cell Biol. 24, 4791–4800 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Barlaskar, F. M. et al. Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 94, 204–212 (2009).

    CAS  PubMed  Google Scholar 

  69. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT00831844 (2015).

  70. Fassnacht, M. 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. 16, 426–35 (2015).

    CAS  PubMed  Google Scholar 

  71. Sasano, H., Satoh, F. & Nakamura, Y. Roles of the pathologist in evaluating surrogate markers for medical therapy in adrenocortical carcinoma. Endocr. Pathol. 25, 366–370 (2014).

    CAS  PubMed  Google Scholar 

  72. Adam, P. et al. Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome. Mod. Pathol. 23, 1596–1604 (2010).

    CAS  PubMed  Google Scholar 

  73. Quinkler, M. et al. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J. Clin. Endocrinol. Metab. 93, 2057–2062 (2008).

    CAS  PubMed  Google Scholar 

  74. Ardolino, L., Hansen, A., Ackland, S. & Joshua, A. Advanced adrenocortical carcinoma (ACC): a review with focus on second-line therapies. Horm. Cancer 11, 155–169 (2020).

    PubMed  PubMed Central  Google Scholar 

  75. Boumahdi, S. & de Sauvage, F. J. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 19, 39–56 (2020).

    CAS  PubMed  Google Scholar 

  76. Quintanal-Villalonga, Á. et al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat. Rev. Clin. Oncol. 17, 360–371 (2020).

    PubMed  PubMed Central  Google Scholar 

  77. Gara, S. K. et al. Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors. Nat. Commun. 9, 4172 (2018). This study demonstrates that genomic alterations between primary adrenocortical carcinoma and recurrent and metastatic adrenocortical carcinoma are different with the latter exhibiting more tumour heterogeneity.

    PubMed  PubMed Central  Google Scholar 

  78. Heaton, J. H. et al. Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin. Am. J. Pathol. 181, 1017–1033 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Berthon, A. et al. Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum. Mol. Genet. 19, 1561–1576 (2010).

    CAS  PubMed  Google Scholar 

  80. Lin, S. & Gregory, R. I. MicroRNA biogenesis pathways in cancer. Nat. Rev. Cancer 15, 321–333 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Huarte, M. The emerging role of lncRNAs in cancer. Nat. Med. 21, 1253–1261 (2015).

    CAS  PubMed  Google Scholar 

  82. Liu, J., Kahri, A. I., Heikkila, P., Ilvesmaki, V. & Voutilainen, R. H19 and insulin-like growth factor-II gene expression in adrenal tumors and cultured adrenal cells. J. Clin. Endocrinol. Metab. 80, 492–496 (1995).

    CAS  PubMed  Google Scholar 

  83. Hatada, I. & Mukai, T. Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse. Nat. Genet. 11, 204–206 (1995).

    CAS  PubMed  Google Scholar 

  84. Liu, J., Kahri, A. I., Heikkila, P. & Voutilainen, R. Ribonucleic acid expression of the clustered imprinted genes, p57KIP2, insulin-like growth factor II, and H19, in adrenal tumors and cultured adrenal cells. J. Clin. Endocrinol. Metab. 82, 1766–1771 (1997).

    CAS  PubMed  Google Scholar 

  85. Soon, P. S. et al. miR-195 and miR-483-5p identified as predictors of poor prognosis in adrenocortical cancer. Clin. Cancer Res. 15, 7684–7692 (2009).

    CAS  PubMed  Google Scholar 

  86. Feinmesser, M. et al. Specific microRNAs differentiate adrenocortical adenomas from carcinomas and correlate with Weiss histopathologic system. Appl. Immunohistochem. Mol. Morphol. 23, 522–531 (2015).

    CAS  PubMed  Google Scholar 

  87. Koperski, Ł. et al. Next-generation sequencing reveals microRNA markers of adrenocortical tumors malignancy. Oncotarget 8, 49191–49200 (2017).

    PubMed  PubMed Central  Google Scholar 

  88. Chehade, M., Bullock, M., Glover, A., Hutvagner, G. & Sidhu, S. Key microRNA’s and their targetome in adrenocortical cancer. Cancers 12, 2198 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Mitchell, P. S. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105, 10513–10518 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Chabre, O. et al. Serum miR-483-5p and miR-195 are predictive of recurrence risk in adrenocortical cancer patients. Endocr. Relat. Cancer 20, 579–594 (2013).

    CAS  PubMed  Google Scholar 

  91. Szabó, D. R. et al. Analysis of circulating microRNAs in adrenocortical tumors. Lab. Invest. 94, 331–339 (2014).

    PubMed  Google Scholar 

  92. Patel, D. et al. MiR-34a and miR-483-5p are candidate serum biomarkers for adrenocortical tumors. Surgery 154, 1224–1228 (2013). 

    PubMed  Google Scholar 

  93. Wu, Y. et al. MicroRNA-205 suppresses the growth of adrenocortical carcinoma SW-13 cells via targeting Bcl-2. Oncol. Rep. 34, 3104–3110 (2015).

    PubMed  Google Scholar 

  94. Jain, M. et al. ZNF367 inhibits cancer progression and is targeted by miR-195. PLoS ONE 9, e101423 (2014).

    PubMed  PubMed Central  Google Scholar 

  95. Kwok, G. T. Y. et al. microRNA-431 as a chemosensitizer and potentiator of drug activity in adrenocortical carcinoma. Oncologist 24, e241–e250 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Hassan, N., Zhao, J. T., Glover, A., Robinson, B. G. & Sidhu, S. B. Reciprocal interplay of miR-497 and MALAT1 promotes tumourigenesis of adrenocortical cancer. Endocr. Relat. Cancer 26, 677–688 (2019).

    CAS  PubMed  Google Scholar 

  97. Kalinowski, F. C. et al. microRNA-7: a tumor suppressor miRNA with therapeutic potential. Int. J. Biochem. Cell Biol. 54, 312–317 (2014).

    CAS  PubMed  Google Scholar 

  98. Gara, S. K. et al. Integrated genome-wide analysis of genomic changes and gene regulation in human adrenocortical tissue samples. Nucleic Acids Res. 43, 9327–9339 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Glover, A. R. et al. Long noncoding RNA profiles of adrenocortical cancer can be used to predict recurrence. Endocr. Relat. Cancer 22, 99–109 (2015). One of the first studies to show that the lncRNA expression profile of adrenocortical carcinoma is different from that of benign adrenocortical carcinoma and normal adrenal cortex.

    CAS  PubMed  Google Scholar 

  100. Buishand, F. O. et al. Adrenocortical tumors have a distinct, long, non-coding RNA expression profile and LINC00271 is downregulated in malignancy. Surgery 167, 224–232 (2020).

    PubMed  Google Scholar 

  101. Long, B. et al. Long noncoding RNA ASB16-AS1 inhibits adrenocortical carcinoma cell growth by promoting ubiquitination of RNA-binding protein HuR. Cell Death Dis. 11, 995 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Guo, N., Sun, Q., Fu, D. & Zhang, Y. Long non-coding RNA UCA1 promoted the growth of adrenocortical cancer cells via modulating the miR-298-CDK6 axis. Gene 703, 26–34 (2019).

    CAS  PubMed  Google Scholar 

  103. Tombol, Z. et al. Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis. Endocr. Relat. Cancer 16, 895–906 (2009).

    CAS  PubMed  Google Scholar 

  104. Duregon, E. et al. MicroRNA expression patterns in adrenocortical carcinoma variants and clinical pathologic correlations. Hum. Pathol. 45, 1555–1562 (2014).

    CAS  PubMed  Google Scholar 

  105. Ozata, D. M. et al. The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma. Endocr. Relat. Cancer 18, 643–655 (2011).

    PubMed  PubMed Central  Google Scholar 

  106. Patterson, E. E., Holloway, A. K., Weng, J., Fojo, T. & Kebebew, E. MicroRNA profiling of adrenocortical tumors reveals miR-483 as a marker of malignancy. Cancer 117, 1630–1639 (2011).

    CAS  PubMed  Google Scholar 

  107. Ettaieb, M., Kerkhofs, T., van Engeland, M. & Haak, H. Past, present and future of epigenetics in adrenocortical carcinoma. Cancers 12, 1218 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Rechache, N. S. et al. DNA methylation profiling identifies global methylation differences and markers of adrenocortical tumors. J. Clin. Endocrinol. Metab. 97, E1004–E1013 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Creemers, S. G. et al. Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas. Endocr. Relat. Cancer 23, 727–737 (2016).

    CAS  PubMed  Google Scholar 

  110. Barreau, O. et al. Identification of a CpG island methylator phenotype in adrenocortical carcinomas. J. Clin. Endocrinol. Metab. 98, E174–E184 (2013).

    CAS  PubMed  Google Scholar 

  111. Jouinot, A. et al. DNA methylation is an independent prognostic marker of survival in adrenocortical cancer. J. Clin. Endocrinol. Metab. 102, 923–932 (2017).

    PubMed  Google Scholar 

  112. Lippert, J. et al. Prognostic role of targeted methylation analysis in paraffin-embedded samples of adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 107, 2892–2899 (2022).

    PubMed  PubMed Central  Google Scholar 

  113. Mohan, D. R. et al. Targeted assessment of G0S2 methylation identifies a rapidly recurrent, routinely fatal molecular subtype of adrenocortical carcinoma. Clin. Cancer Res. 25, 3276–3288 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Clay, M. R. et al. DNA methylation profiling reveals prognostically significant groups in pediatric adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. JCO Precis. Oncol. 3, PO.19.00163 (2019).

    PubMed  PubMed Central  Google Scholar 

  115. Drelon, C. et al. EZH2 is overexpressed in adrenocortical carcinoma and is associated with disease progression. Hum. Mol. Genet. 25, 2789–2800 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Tabbal, H. et al. EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness. Br. J. Cancer 121, 384–394 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Kebebew, E. Adrenal incidentaloma. N. Engl. J. Med. 384, 1542–1551 (2021).

    PubMed  Google Scholar 

  118. Rege, J., Turcu, A. F., Else, T., Auchus, R. J. & Rainey, W. E. Steroid biomarkers in human adrenal disease. J. Steroid Biochem. Mol. Biol. 190, 273–280 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Taylor, D. R. et al. A 13-steroid serum panel based on LC-MS/MS: use in detection of adrenocortical carcinoma. Clin. Chem. 63, 1836–1846 (2017). Along with Rege et al. (2019), this study shows the utility of measuring levels of steroids and their metabolities as biomarkers of adrenocortical carcinoma.

    CAS  PubMed  Google Scholar 

  120. Chortis, V. et al. Urine steroid metabolomics as a novel tool for detection of recurrent adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 105, e307–e318 (2020).

    PubMed  Google Scholar 

  121. Suzuki, S. et al. Steroid metabolites for diagnosing and predicting clinicopathological features in cortisol-producing adrenocortical carcinoma. BMC Endocr. Disord. 20, 173 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Bancos, I. et al. Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study. Lancet Diabetes Endocrinol. 8, 773–781 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Patel, D. et al. Unique and novel urinary metabolomic features in malignant versus benign adrenal neoplasms. Clin. Cancer Res. 23, 5302–5310 (2017). This study shows that patients with adrenocortical carcinoma have a unique urinary metabolome, which derives from the tumour tissue.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Mathe, E. A. et al. Noninvasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer. Cancer Res. 74, 3259–3270 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Haznadar, M. et al. Urinary metabolites diagnostic and prognostic of intrahepatic cholangiocarcinoma. Cancer Epidemiol. Biomark. Prev. 28, 1704–1711 (2019).

    CAS  Google Scholar 

  126. Foster, P. A. & Mueller, J. W. SULFATION PATHWAYS: insights into steroid sulfation and desulfation pathways. J. Mol. Endocrinol. 61, T271–T283 (2018).

    CAS  PubMed  Google Scholar 

  127. Sun, N. et al. Prognostic relevance of steroid sulfation in adrenocortical carcinoma revealed by molecular phenotyping using high-resolution mass spectrometry imaging. Clin. Chem. 65, 1276–1286 (2019).

    CAS  PubMed  Google Scholar 

  128. Sigala, S. et al. A comprehensive investigation of steroidogenic signaling in classical and new experimental cell models of adrenocortical carcinoma. Cells 11, 1439 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Fujisawa, Y. et al. Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma. J. Steroid Biochem. Mol. Biol. 159, 86–93 (2016).

    CAS  PubMed  Google Scholar 

  130. Marti, N. et al. Androgen production in pediatric adrenocortical tumors may occur via both the classic and/or the alternative backdoor pathway. Mol. Cell Endocrinol. 452, 64–73 (2017).

    CAS  PubMed  Google Scholar 

  131. Fenske, W. et al. Glucose transporter GLUT1 expression is an stage-independent predictor of clinical outcome in adrenocortical carcinoma. Endocr. Relat. Cancer 16, 919–928 (2009).

    PubMed  Google Scholar 

  132. Satoh, K., Patel, D., Dieckmann, W., Nilubol, N. & Kebebew, E. Whole body metabolic tumor volume and total lesion glycolysis predict survival in patients with adrenocortical carcinoma. Ann. Surg. Oncol. 22 (Suppl. 3), S714–S720 (2015).

    PubMed  Google Scholar 

  133. Wrenn, S. M. et al. Higher SUVmax on FDG-PET is associated with shorter survival in adrenocortical carcinoma. Am. J. Surg. 225, 309–314 (2023).

    PubMed  Google Scholar 

  134. Pinheiro, C. et al. GLUT1 expression in pediatric adrenocortical tumors: a promising candidate to predict clinical behavior. Oncotarget 8, 63835–63845 (2017).

    PubMed  PubMed Central  Google Scholar 

  135. Assié, G. et al. Value of molecular classification for prognostic assessment of adrenocortical carcinoma. JAMA Oncol. 5, 1440–1447 (2019).

    PubMed  Google Scholar 

  136. de Reyniès, A. et al. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J. Clin. Oncol. 27, 1108–1115 (2009).

    PubMed  Google Scholar 

  137. Marquardt, A. et al. Identifying new potential biomarkers in adrenocortical tumors based on mrna expression data using machine learning. Cancers 13, 4671 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Yi, X. et al. Identification of four novel prognostic biomarkers and construction of two nomograms in adrenocortical carcinoma: a multi-omics data study via bioinformatics and machine learning methods. Front. Mol. Biosci. 9, 878073 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Paré, L. et al. Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types. Ann. Oncol. 29, 2121–2128 (2018).

    PubMed  Google Scholar 

  140. Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830.e14 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Mohan, D. R., Lerario, A. M. & Hammer, G. D. Therapeutic targets for adrenocortical carcinoma in the genomics era. J. Endocr. Soc. 2, 1259–1274 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Tian, X. et al. Identification of tumor-infiltrating immune cells and prognostic validation of tumor-infiltrating mast cells in adrenocortical carcinoma: results from bioinformatics and real-world data. Oncoimmunology 9, 1784529 (2020).

    PubMed  PubMed Central  Google Scholar 

  143. Newman, A. M. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453–457 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Landwehr, L. S. et al. Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma. J. Immunother. Cancer 8, e000469 (2020).

    PubMed  PubMed Central  Google Scholar 

  145. Coutinho, A. E. & Chapman, K. E. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol. Cell Endocrinol. 335, 2–13 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Marx, C., Wolkersdorfer, G. W., Brown, J. W., Scherbaum, W. A. & Bornstein, S. R. MHC class II expression—a new tool to assess dignity in adrenocortical tumours. J. Clin. Endocrinol. Metab. 81, 4488–4491 (1996).

    CAS  PubMed  Google Scholar 

  147. Ozdemirli, M. et al. Fas (CD95)/Fas ligand interactions regulate antigen-specific, major histocompatibility complex-restricted T/B cell proliferative responses. Eur. J. Immunol. 26, 415–419 (1996).

    CAS  PubMed  Google Scholar 

  148. Brunner, T. et al. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373, 441–444 (1995).

    CAS  PubMed  Google Scholar 

  149. Wolkersdörfer, G. W. et al. Prevalence of HLA-DRB1 genotype and altered Fas/Fas ligand expression in adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 90, 1768–1774 (2005).

    PubMed  Google Scholar 

  150. Hahne, M. et al. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274, 1363–1366 (1996).

    CAS  PubMed  Google Scholar 

  151. Xiao, W. et al. Loss of fas expression and function is coupled with colon cancer resistance to immune checkpoint inhibitor immunotherapy. Mol. Cancer Res. 17, 420–430 (2019).

    CAS  PubMed  Google Scholar 

  152. Pinto, E. M. et al. Prognostic significance of major histocompatibility complex class ii expression in pediatric adrenocortical tumors: a St. Jude and Children’s Oncology Group Study. Clin. Cancer Res. 22, 6247–6255 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Kanczkowski, W. et al. Abrogation of TLR4 and CD14 expression and signaling in human adrenocortical tumors. J. Clin. Endocrinol. Metab. 95, E421–E429 (2010).

    CAS  PubMed  Google Scholar 

  154. Huang, B. et al. Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 65, 5009–5014 (2005).

    CAS  PubMed  Google Scholar 

  155. Szajnik, M. et al. TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene 28, 4353–4363 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Liang, J. et al. Clinicopathological and prognostic characteristics of CD276 (B7-H3) expression in adrenocortical carcinoma. Dis. Markers 2020, 5354825 (2020).

    PubMed  PubMed Central  Google Scholar 

  157. Hofmeyer, K. A., Ray, A. & Zang, X. The contrasting role of B7-H3. Proc. Natl Acad. Sci. USA 105, 10277–10278 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Liao, H., Ding, M., Zhou, N., Yang, Y. & Chen, L. B7-H3 promotes the epithelial-mesenchymal transition of NSCLC by targeting SIRT1 through the PI3K/AKT pathway. Mol. Med. Rep. 25, 79 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Raj, N. et al. PD-1 blockade in advanced adrenocortical carcinoma. J. Clin. Oncol. 38, 71–80 (2020).

    CAS  PubMed  Google Scholar 

  160. Habra, M. A. et al. Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. J. Immunother. Cancer 7, 253 (2019).

    PubMed  PubMed Central  Google Scholar 

  161. Head, L. et al. Response to immunotherapy in combination with mitotane in patients with metastatic adrenocortical cancer. J. Endocr. Soc. 3, 2295–2304 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Bedrose, S. et al. Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma. J. Immunother. Cancer 8, e001009 (2020).

    PubMed  PubMed Central  Google Scholar 

  163. Carneiro, B. A. et al. Nivolumab in metastatic adrenocortical carcinoma: results of a phase 2 trial. J. Clin. Endocrinol. Metab. 104, 6193–6200 (2019).

    PubMed  Google Scholar 

  164. McGregor, B. A. et al. Results of a multicenter, phase 2 study of nivolumab and ipilimumab for patients with advanced rare genitourinary malignancies. Cancer 127, 840–849 (2021).

    CAS  PubMed  Google Scholar 

  165. Grondal, S., Eriksson, B., Hagenas, L., Werner, S. & Curstedt, T. Steroid profile in urine: a useful tool in the diagnosis and follow up of adrenocortical carcinoma. Acta Endocrinol. 122, 656–663 (1990).

    CAS  Google Scholar 

  166. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04373265 (2023).

  167. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04187404 (2023).

  168. Armignacco, R. et al. The adipose stem cell as a novel metabolic actor in adrenocortical carcinoma progression: evidence from an in vitro tumor microenvironment crosstalk model. Cancers 11, 1931 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Jain, M. et al. TOP2A is overexpressed and is a therapeutic target for adrenocortical carcinoma. Endocr. Relat. Cancer 20, 361–370 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Satoh, K. et al. Identification of niclosamide as a novel anticancer agent for adrenocortical carcinoma. Clin. Cancer Res. 22, 3458–3466 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Jain, M. et al. Interleukin-13 receptor alpha2 is a novel therapeutic target for human adrenocortical carcinoma. Cancer 118, 5698–5708 (2012).

    CAS  PubMed  Google Scholar 

  172. Barton, D. E., Foellmer, B. E., Wood, W. I. & Francke, U. Chromosome mapping of the growth hormone receptor gene in man and mouse. Cytogenet. Cell Genet. 50, 137–141 (1989).

    CAS  PubMed  Google Scholar 

  173. Hantel, C. et al. Targeting heterogeneity of adrenocortical carcinoma: evaluation and extension of preclinical tumor models to improve clinical translation. Oncotarget 7, 79292–79304 (2016).

    PubMed  PubMed Central  Google Scholar 

  174. Cardoso, C. C., Bornstein, S. R. & Hornsby, P. J. Optimizing orthotopic cell transplantation in the mouse adrenal gland. Cell Transpl. 19, 565–572 (2010).

    Google Scholar 

  175. Ruggiero, C., Doghman-Bouguerra, M. & Lalli, E. How good are the current models of adrenocortical carcinoma for novel drug discovery? Expert Opin. Drug Discov. 17, 211–213 (2022).

    CAS  PubMed  Google Scholar 

  176. Batisse-Lignier, M. et al. p53/Rb inhibition induces metastatic adrenocortical carcinomas in a preclinical transgenic model. Oncogene 36, 4445–4456 (2017). This study demonstrates that known genetic alterations in human adrenocortical carcinoma introduced into a mouse can cause adrenocortical carcinoma similar in phenotype and histology to those human tumours and that this mouse model can in turn be used to evaluate the efficacy of targeted therapies.

    CAS  PubMed  Google Scholar 

  177. Borges, K. S. et al. Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice. Oncogene 39, 5282–5291 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Warde, K. M. et al. Senescence-induced immune remodeling facilitates metastatic adrenal cancer in a sex-dimorphic manner. Nat. Aging 3, 846–865 (2023).

    CAS  PubMed  Google Scholar 

  179. Wilmouth, J. J. Jr. et al. Sexually dimorphic activation of innate antitumor immunity prevents adrenocortical carcinoma development. Sci. Adv. 8, eadd0422 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Lyraki, R. et al. Crosstalk between androgen receptor and WNT/β-catenin signaling causes sex-specific adrenocortical hyperplasia in mice. Dis. Model. Mech. 16, dmm050053 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Kiseljak-Vassiliades, K. et al. Development of new preclinical models to advance adrenocortical carcinoma research. Endocr. Relat. Cancer 25, 437–451 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Lang, J. et al. Development of an adrenocortical cancer humanized mouse model to characterize anti-pd1 effects on tumor microenvironment. J. Clin. Endocrinol. Metab. 105, 26–42 (2020). This study develops a humanized adrenocortical carcinoma PDX mouse model to assess immunotherapy responses.

    PubMed  Google Scholar 

  183. Pinto, E. M. et al. Establishment and characterization of the first pediatric adrenocortical carcinoma xenograft model identifies topotecan as a potential chemotherapeutic agent. Clin. Cancer Res. 19, 1740–1747 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Fiorentini, C. et al. Palbociclib inhibits proliferation of human adrenocortical tumor cells. Endocrine 59, 213–217 (2018).

    CAS  PubMed  Google Scholar 

  185. Liang, R. et al. Targeted gene expression profile reveals CDK4 as therapeutic target for selected patients with adrenocortical carcinoma. Front. Endocrinol. 11, 219 (2020).

    Google Scholar 

  186. Hadjadj, D. et al. A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas. Aging 9, 2695–2716 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Nilubol, N. et al. Synergistic combination of flavopiridol and carfilzomib targets commonly dysregulated pathways in adrenocortical carcinoma and has biomarkers of response. Oncotarget 9, 33030–33042 (2018).

    PubMed  PubMed Central  Google Scholar 

  188. Doghman, M. et al. Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res. 70, 4666–4675 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Doghman, M., Cazareth, J. & Lalli, E. The T cell factor/beta-catenin antagonist PKF115-584 inhibits proliferation of adrenocortical carcinoma cells. J. Clin. Endocrinol. Metab. 93, 3222–3225 (2008).

    CAS  PubMed  Google Scholar 

  190. Gaujoux, S. et al. Silencing mutated β-catenin inhibits cell proliferation and stimulates apoptosis in the adrenocortical cancer cell line H295R. PLoS ONE 8, e55743 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Cerquetti, L. et al. Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells. Exp. Cell Res. 317, 1397–1410 (2011).

    CAS  PubMed  Google Scholar 

  192. Cantini, G. et al. Rosiglitazone inhibits adrenocortical cancer cell proliferation by interfering with the IGF-IR intracellular signaling. PPAR Res. 2008, 904041 (2008).

    PubMed  PubMed Central  Google Scholar 

  193. Ferruzzi, P. et al. Thiazolidinediones inhibit growth and invasiveness of the human adrenocortical cancer cell line H295R. J. Clin. Endocrinol. Metab. 90, 1332–1339 (2005).

    CAS  PubMed  Google Scholar 

  194. Sirianni, R. et al. Targeting estrogen receptor-α reduces adrenocortical cancer (ACC) cell growth in vitro and in vivo: potential therapeutic role of selective estrogen receptor modulators (SERMs) for ACC treatment. J. Clin. Endocrinol. Metab. 97, E2238–E2250 (2012).

    CAS  PubMed  Google Scholar 

  195. Chimento, A. et al. GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo. Oncotarget 6, 19190–19203 (2015).

    PubMed  PubMed Central  Google Scholar 

  196. Casaburi, I. et al. Estrogen related receptor α (ERRα) a promising target for the therapy of adrenocortical carcinoma (ACC). Oncotarget 6, 25135–25148 (2015).

    PubMed  PubMed Central  Google Scholar 

  197. Tamburello, M. et al. Preclinical evidence of progesterone as a new pharmacological strategy in human adrenocortical carcinoma cell lines. Int. J. Mol. Sci. 24, 6829 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Doghman, M. et al. Inhibition of adrenocortical carcinoma cell proliferation by steroidogenic factor-1 inverse agonists. J. Clin. Endocrinol. Metab. 94, 2178–2183 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Cheng, Y., Kerppola, R. E. & Kerppola, T. K. ATR-101 disrupts mitochondrial functions in adrenocortical carcinoma cells and in vivo. Endocr. Relat. Cancer 23, 1–19 (2016).

    PubMed  PubMed Central  Google Scholar 

  200. LaPensee, C. R. et al. ATR-101, a selective and potent inhibitor of acyl-CoA acyltransferase 1, induces apoptosis in h295r adrenocortical cells and in the adrenal cortex of dogs. Endocrinology 157, 1775–1788 (2016).

    CAS  PubMed  Google Scholar 

  201. Subramanian, C. et al. Synthetic high-density lipoprotein nanoparticles: a novel therapeutic strategy for adrenocortical carcinomas. Surgery 159, 284–294 (2016).

    PubMed  Google Scholar 

  202. Bussey, K. J. et al. Targeting polo-like kinase 1, a regulator of p53, in the treatment of adrenocortical carcinoma. Clin. Transl. Med. 5, 1 (2016).

    PubMed  PubMed Central  Google Scholar 

  203. Martarelli, D., Pompei, P., Baldi, C. & Mazzoni, G. Mebendazole inhibits growth of human adrenocortical carcinoma cell lines implanted in nude mice. Cancer Chemother. Pharmacol. 61, 809–817 (2008).

    CAS  PubMed  Google Scholar 

  204. Poli, G. et al. Metformin as a new anti-cancer drug in adrenocortical carcinoma. Oncotarget 7, 49636–49648 (2016).

    PubMed  PubMed Central  Google Scholar 

  205. Glover, A. R. et al. MicroRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma. Oncotarget 6, 36675–36688 (2015).

    PubMed  PubMed Central  Google Scholar 

  206. Babińska, A., Pęksa, R., Wiśniewski, P., Świątkowska-Stodulska, R. & Sworczak, K. Diagnostic and prognostic role of SF1, IGF2, Ki67, p53, adiponectin, and leptin receptors in human adrenal cortical tumors. J. Surg. Oncol. 116, 427–433 (2017).

    PubMed  Google Scholar 

  207. Liu, S., Ding, G., Zhou, Z. & Feng, C. β-Catenin-driven adrenocortical carcinoma is characterized with immune exclusion. Onco Targets Ther. 11, 2029–2036 (2018).

    PubMed  PubMed Central  Google Scholar 

  208. Pennanen, M. et al. C-myc expression in adrenocortical tumours. J. Clin. Pathol. 71, 129–134 (2018).

    CAS  PubMed  Google Scholar 

  209. Fernandez-Ranvier, G. G. et al. Identification of biomarkers of adrenocortical carcinoma using genomewide gene expression profiling. Arch. Surg. 143, 841–846 (2008).

    PubMed  Google Scholar 

  210. Aporowicz, M. et al. Minichromosome maintenance proteins MCM-3, MCM-5, MCM-7, and Ki-67 as proliferative markers in adrenocortical tumors. Anticancer Res. 39, 1151–1159 (2019).

    CAS  PubMed  Google Scholar 

  211. Cheng, Y., Kou, W., Zhu, D., Yu, X. & Zhu, Y. Future directions in diagnosis, prognosis and disease monitoring of adrenocortical carcinoma: novel non-invasive biomarkers. Front. Endocrinol. 12, 811293 (2021).

    Google Scholar 

  212. Mytareli, C. et al. The diagnostic, prognostic and therapeutic role of mirnas in adrenocortical carcinoma: a systematic review. Biomedicines 9, 1501 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Cantini, G. et al. Prognostic and monitoring value of circulating tumor cells in adrenocortical carcinoma: a preliminary monocentric study. Cancers 12, 3176 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Creemers, S. G. et al. Identification of mutations in cell-free circulating tumor DNA in adrenocortical carcinoma: a case series. J. Clin. Endocrinol. Metab. 102, 3611–3615 (2017).

    PubMed  Google Scholar 

  215. Zhang, F. et al. Prognostic role of Ki-67 in adrenocortical carcinoma after primary resection: a retrospective mono-institutional study. Adv. Ther. 36, 2756–2768 (2019).

    CAS  PubMed  Google Scholar 

  216. Xu, W. H. et al. Screening and identification of potential prognostic biomarkers in adrenocortical carcinoma. Front. Genet. 10, 821 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Fragoso, M. C. et al. Combined expression of BUB1B, DLGAP5, and PINK1 as predictors of poor outcome in adrenocortical tumors: validation in a Brazilian cohort of adult and pediatric patients. Eur. J. Endocrinol. 166, 61–67 (2012).

    CAS  PubMed  Google Scholar 

  218. Sbiera, S. et al. Assessment of VAV2 expression refines prognostic prediction in adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 102, 3491–3498 (2017).

    PubMed  Google Scholar 

  219. Faria, A. M. & Almeida, M. Q. Differences in the molecular mechanisms of adrenocortical tumorigenesis between children and adults. Mol. Cell Endocrinol. 351, 52–57 (2012).

    CAS  PubMed  Google Scholar 

  220. Sbiera, S. et al. High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J. Clin. Endocrinol. Metab. 95, E161–E171 (2010).

    CAS  PubMed  Google Scholar 

  221. Miller, B. S., Gauger, P. G., Hammer, G. D., Giordano, T. J. & Doherty, G. M. Proposal for modification of the ENSAT staging system for adrenocortical carcinoma using tumor grade. Langenbecks Arch. Surg. 395, 955–961 (2010).

    PubMed  Google Scholar 

  222. Mermejo, L. M. et al. Altered expression of noncanonical Wnt pathway genes in paediatric and adult adrenocortical tumours. Clin. Endocrinol. 81, 503–510 (2014).

    CAS  Google Scholar 

  223. Lavoie, J. M. et al. Whole-genome and transcriptome analysis of advanced adrenocortical cancer highlights multiple alterations affecting epigenome and DNA repair pathways. Cold Spring Harb. Mol. Case Stud. 8, a006148 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Legendre, C. R. et al. pathway implications of aberrant global methylation in adrenocortical cancer. PLoS ONE 11, e0150629 (2016).

    PubMed  PubMed Central  Google Scholar 

  225. Fonseca, A. L. et al. Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors. Genes Chromosomes Cancer 51, 949–960 (2012).

    CAS  PubMed  Google Scholar 

  226. Gao, Z. H. et al. Association of H19 promoter methylation with the expression of H19 and IGF-II genes in adrenocortical tumors. J. Clin. Endocrinol. Metab. 87, 1170–1176 (2002).

    CAS  PubMed  Google Scholar 

  227. Arlt, W. et al. Urine steroid metabolomics as a biomarker tool for detecting malignancy in adrenal tumors. J. Clin. Endocrinol. Metab. 96, 3775–3784 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank G. Kalafatis for her help with organizing the manuscript draft and for management of the references for the manuscript. The authors apologize to colleagues whose work they may not have cited given the space constraint for the article.

Author information

Authors and Affiliations

  1. Department of Surgery, Stanford University, Stanford, CA, USA

    Chandrayee Ghosh, Jiangnan Hu & Electron Kebebew

  2. Stanford Cancer Institute, Stanford University, Stanford, CA, USA

    Electron Kebebew

Authors
  1. Chandrayee Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiangnan Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Electron Kebebew
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Electron Kebebew.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cancer thanks Michael Fassnacht, Joakim Crona, who co-reviewed with Liang Zhang, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Area under the receiver operating characteristic (ROC) curve

(AUC). A statistical analysis used to measure the diagnostic accuracy of a test. The y axis represents the sensitivity (true positive rate) and the x axis represents 1 − specificity (true negative rate) of the test when using different cut-off values of the value measured. The closer the curve is to the left upper corner of the graph the more accurate the test is. Thus, a test with an AUC = 1 is perfect and a test with an AUC = 0.5 is completely random.

Classical subtype

The common histological subtype based on microscopic features of eosinophilic cytoplasm, often with thick fibrous bands and capsule, necrosis and mitotic figures.

Cushing syndrome

A disorder that is due to overproduction of cortisol over a prolonged period; also called hypercortisolism.

Decision curve analysis

A method of statistical analysis to evaluate prediction models, diagnostic tests and molecular markers.

Genomic imprinting

A mechanism of silencing of a gene in which the repressed allele is methylated and the active allele is unmethylated.

Helsinki scoring system

A system for diagnosis and prognosis based on evaluation of a combination of morphological (mitoses and necrosis) and immunohistochemical (Ki-67) parameters in patients.

Leydig cells

Cells in the testis that are the primary source of testosterone.

Lin–Weiss–Bisceglia system

A modified Weiss scoring system, which recommends that for oncocytic adrenocortical neoplasms, a malignancy can be indicated in the presence of one major criterion and indicated as uncertain in the presence of only minor criteria or considered as benign in the absence of both major and minor criteria.

Lynch syndrome

An inherited cancer syndrome that often genetically predisposes the patient to different types of cancer, especially colorectal cancer. Hence, it is also referred to as hereditary non-polyposis colorectal cancer.

Metabolic tumour volume

(MTV). A measurement of the metabolically active tumour volume based on tumour segmentation for the amount of 18F-fluorodeoxyglucose taken up on PET.

Myxoid subtype

When observed by microscopy, frequent cords or trabeculae of tumour cells appear floating in the stroma with diffuse pools or a lack of extracellular mucin. The tumour mucin is positive for Alcian blue.

Nomograms

Graphical calculating devices enabling an approximate graphical computation of a mathematical model predicting the relationship between variables and the probability of the outcome associated with those variables.

Oncocytic subtype

When observed by microscopy, abundant granular eosinophilic cytoplasm, excessive number of mitochondria and high-grade nuclear features are present. Frequent atypical mitotic figures and intranuclear inclusions are also observed.

Primary hyperaldosteronism

A disorder that is due to overproduction and release of aldosterone from the adrenal glands.

Reticulin algorithm

Distinguishes malignancy through an altered reticulin framework (a type of fibre in connective tissue composed of type III collagen in which these reticular fibres crosslink to form a fine meshwork) associated with either necrosis, a high mitotic rate or vascular invasion.

Sarcomatoid subtype

When observed by microscopy, frequent spindle tumour cells as well as giant cells are present. There is also prominent nuclear pleomorphism and atypical mitotic figures.

Scoring systems of Weiss et al.

The reference scoring method to distinguish between benign and malignant adrenocortical tumours in adults based on positive scores for features related to, for example, architecture, nucleus and the presence of any type of invasion, with each feature given a score of 1. A total score of 3 or more indicates a malignant tumour.

Standardized uptake value

(SUV). A semi-quantitative measure of the amount of 18F-fluorodeoxyglucose taken up by a tumour with PET. The value is determined by the ratio of activity per unit volume of a region of interest to the activity per unit whole body volume. SUVs are reported as the mean (the average over the region of interest) and the maximum (the highest in the region of interest).

Steroid sulfation

The sulfation of endogenous steroids. In general, sulfated steroids are not able to bind and activate their target nuclear receptors and also require active transport into cells by an anion transporter as they are no longer lipophilic owing to the sulfation.

SV40 large T antigen

A dominant-acting oncoprotein derived from the polyomavirus SV40 and capable of inducing malignant transformation of various cell types. The transforming activity of this oncoprotein is largely due to its dysregulation of RB and p53.

Telomere maintenance pathway

The molecular pathway that regulates telemore length, which is essential for cancer cells to proliferate and not undergo senescence or apoptosis.

Total lesion glycolysis

(TLG). The product of the standardized uptake value and metabolic tumour volume, which more accurately reflects the glycolytic phenotype of a tumour and is associated with prognosis in several types of cancer.

Virilization

The acquisition of adult male physical features that develop in a female or young male, precociously, owing to excess androgen production.

Weighted correlation network analysis

(WGCNA). A widely used data mining method used especially for biological networks based on pairwise correlations between variables.

Wieneke criteria

A scoring system based on tumour size, local invasion and histological features, which distinguishes between benign and malignant tumours as well as predicts the prognosis of paediatric adrenocortical carcinomas.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghosh, C., Hu, J. & Kebebew, E. Advances in translational research of the rare cancer type adrenocortical carcinoma. Nat Rev Cancer 23, 805–824 (2023). https://doi.org/10.1038/s41568-023-00623-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-023-00623-0

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer