Reviews in Endocrine and Metabolic Disorders

, Volume 8, Issue 4, pp 343–348 | Cite as

The molecular genetics of adrenocortical carcinoma

  • Ferdous M. Barlaskar
  • Gary D. Hammer


Adrenocortical carcinoma (ACC) is a rare endocrine malignancy defined by a heterogeneous clinical presentation, dismal prognosis, and lack of effective therapeutic regimens. The incidence of ACC ranges from 0.5 to 2 cases per million people per year, accounting for 0.02% of all reported cancers [1]. Unfortunately, most patients present with metastatic disease which reduces the 5 year survival rate to less than 10% [2]. The resultant limited clinical experience has hampered significant research interest, public awareness and overall support from a limited pool of funding agencies. This review aims to summarize emerging genetic and molecular events implicated in the pathogenesis of ACC that can serve to energize current and future efforts to provide effective diagnostic and therapeutic approaches to this deadly cancer.

Epidemiology and clinical management

Adrenal neoplasms are routinely uncovered during medical imaging studies (e.g. abdominal CT scans) performed for other...


Cancer Stem Cell Congenital Adrenal Hyperplasia Adrenocortical Carcinoma Mitotane Carney Complex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Wajchenberg BL, Albergaria Pereira MA, Medonca BB, Latronico AC, Campos Carneiro P, Alves VA, et al. Adrenocortical carcinoma: clinical and laboratory observations. Cancer 2000;88(4):711–36.PubMedCrossRefGoogle Scholar
  2. 2.
    Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B, Chapuis Y, et al. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001;25(7):891–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B. Incidentally discovered adrenal masses. Endocr Rev 1995;16(4):460–84.PubMedCrossRefGoogle Scholar
  4. 4.
    Brunt LM, Moley JF. Adrenal incidentaloma. World J Surg 2001;25(7):905–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Barnett CC Jr., Varma DG, El-Naggar AK, Dackiw AP, Porter GA, Pearson AS, et al. Limitations of size as a criterion in the evaluation of adrenal tumors. Surgery 2000;128(6):973–82; discussion 982–73.PubMedCrossRefGoogle Scholar
  6. 6.
    Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 1993;72(11):3145–55.PubMedCrossRefGoogle Scholar
  7. 7.
    Latronico AC, Chrousos GP. Extensive personal experience: adrenocortical tumors. J Clin Endocrinol Metab 1997;82(5):1317–24.PubMedCrossRefGoogle Scholar
  8. 8.
    Kirschner LS. Signaling pathways in adrenocortical cancer. Ann NY Acad Sci 2002;968:222–39.PubMedCrossRefGoogle Scholar
  9. 9.
    Ahlman H, Khorram-Manesh A, Jansson S, Wangberg B, Nilsson O, Jacobsson CE, et al. Cytotoxic treatment of adrenocortical carcinoma. World J Surg 2001;25(7):927–33.PubMedCrossRefGoogle Scholar
  10. 10.
    Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007;356(23):2372–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr-Relat Cancer 2005;12(3):667–80.PubMedCrossRefGoogle Scholar
  12. 12.
    Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L. Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer. Cancer 1998;83(10):2194–200.PubMedCrossRefGoogle Scholar
  13. 13.
    Khan TS, Imam H, Juhlin C, Skogseid B, Grondal S, Tibblin S, et al. Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann Oncol 2000;11(10):1281–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61(5):759–67.PubMedCrossRefGoogle Scholar
  15. 15.
    Stratakis CA. Genetics of adrenocortical tumors: gatekeepers, landscapers and conductors in symphony. Trends Endocrinol Metab: TEM 2003;14(9):404–10.PubMedCrossRefGoogle Scholar
  16. 16.
    Giordano TJ, Thomas DG, Kuick R, Lizyness M, Misek DE, Smith AL, et al. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 2003;162(2):521–31.PubMedGoogle Scholar
  17. 17.
    Velazquez-Fernandez D, Laurell C, Geli J, Hoog A, Odeberg J, Kjellman M, et al. Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy. Surgery 2005;138(6):1087–94.PubMedCrossRefGoogle Scholar
  18. 18.
    Koch CA, Pacak K, Chrousos GP. The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol Metab 2002;87(12):5367–84.PubMedCrossRefGoogle Scholar
  19. 19.
    Libe R, Bertherat J. Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol 2005;153(4):477–87.PubMedCrossRefGoogle Scholar
  20. 20.
    Ljungman M. Dial 9-1-1 for p53: mechanisms of p53 activation by cellular stress. Neoplasia 2000;2(3):208–25.PubMedCrossRefGoogle Scholar
  21. 21.
    Yano T, Linehan M, Anglard P, Lerman MI, Daniel LN, Stein CA, et al. Genetic changes in human adrenocortical carcinomas. J Natl Cancer Inst 1989;81(7):518–23.PubMedCrossRefGoogle Scholar
  22. 22.
    Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E, et al. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 2001;61(18):6762–7.PubMedGoogle Scholar
  23. 23.
    Sidhu S, Gicquel C, Bambach CP, Campbell P, Magarey C, Robinson BG, et al. Clinical and molecular aspects of adrenocortical tumourigenesis. ANZ J Surg 2003;73(9):727–38.PubMedCrossRefGoogle Scholar
  24. 24.
    Malkin D. The role of p53 in human cancer. J Neuro-Oncol 2001;51(3):231–43.CrossRefGoogle Scholar
  25. 25.
    Zambetti GP. The p53 mutation “gradient effect” and its clinical implications. J Cell Physiol 2007;213(2):370–3.PubMedCrossRefGoogle Scholar
  26. 26.
    Liu G, McDonnell TJ, Montes de Oca Luna R, Kapoor M, Mims B, El-Naggar AK, et al. High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc Natl Acad Sci USA 2000;97(8):4174–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab 1997;82(7):2027–31.PubMedCrossRefGoogle Scholar
  28. 28.
    Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz E, Lafferty AR, et al. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 2001;98(16):9330–5.PubMedCrossRefGoogle Scholar
  29. 29.
    DiGiammarino EL, Lee AS, Cadwell C, Zhang W, Bothner B, Ribeiro RC, et al. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 2002;9(1):12–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 2006;127(7):1323–34.PubMedCrossRefGoogle Scholar
  31. 31.
    Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007;445(7128):661–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007;445(7128):656–60.PubMedCrossRefGoogle Scholar
  33. 33.
    Riedemann J, Macaulay VM. IGF1R signalling and its inhibition. Endocr-Relat Cancer 2006;13(Suppl 1):S33–43.PubMedCrossRefGoogle Scholar
  34. 34.
    Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 2007;28(1):20–47.PubMedCrossRefGoogle Scholar
  35. 35.
    Nolan CM, Kyle JW, Watanabe H, Sly WS. Binding of insulin-like growth factor II (IGF-II) by human cation-independent mannose 6-phosphate receptor/IGF-II receptor expressed in receptor-deficient mouse L cells. Cell Regul 1990;1(2):197–213.PubMedGoogle Scholar
  36. 36.
    Rainey WE, Carr BR, Wang ZN, Parker CR, Jr. Gene profiling of human fetal and adult adrenals. J Endocrinol 2001;171(2):209–15.PubMedCrossRefGoogle Scholar
  37. 37.
    Fottner C, Hoeflich A, Wolf E, Weber MM. Role of the insulin-like growth factor system in adrenocortical growth control and carcinogenesis. Horm Metab Res 2004;36(6):397–405.PubMedCrossRefGoogle Scholar
  38. 38.
    Wiedemann HR. [Familial Malformation Complex with Umbilical Hernia and Macroglossia—a “New Syndrome”?]. J Génét Hum 1964;13:223–32.PubMedGoogle Scholar
  39. 39.
    Weksberg R, Shuman C, Smith AC. Beckwith-Wiedemann syndrome. Am J Med Genet 2005;137(1):12–23.CrossRefGoogle Scholar
  40. 40.
    Pavelic K, Bukovic D, Pavelic J. The role of insulin-like growth factor 2 and its receptors in human tumors. Mol Med Cambridge, Mass 2002;8(12):771–80.Google Scholar
  41. 41.
    Gicquel C, Raffin-Sanson ML, Gaston V, Bertagna X, Plouin PF, Schlumberger M, 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 1997;82(8):2559–65.PubMedCrossRefGoogle Scholar
  42. 42.
    Weber MM, Fottner C, Schmidt P, Brodowski KM, Gittner K, et al. Postnatal overexpression of insulin-like growth factor II in transgenic mice is associated with adrenocortical hyperplasia and enhanced steroidogenesis. Endocrinology 1999;140(4):1537–43.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang P, Liegeois NJ, Wong C, Finegold M, Hou H, Thompson JC, et al. Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature 1997;387(6629):151–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Andrews SC, Wood MD, Tunster SJ, Barton SC, Surani MA, John RM. Cdkn1c (p57Kip2) is the major regulator of embryonic growth within its imprinted domain on mouse distal chromosome 7. BMC Dev Biol 2007;7:53.PubMedCrossRefGoogle Scholar
  45. 45.
    Gabory A, Ripoche MA, Yoshimizu T, Dandolo L. The H19 gene: regulation and function of a non-coding RNA. Cytogenet Genom Res 2006;113(1–4):188–93.CrossRefGoogle Scholar
  46. 46.
    de Fraipont F, El Atifi M, Cherradi N, Le Moigne G, Defaye G, Houlgatte R, et al. Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab 2005;90(3):1819–29.PubMedCrossRefGoogle Scholar
  47. 47.
    West AN, Neale GA, Pounds S, Figueredo BC, Rodriguez Galindo C, Pianovski MA, et al. Gene expression profiling of childhood adrenocortical tumors. Cancer Res 2007;67(2):600–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Slater EP, Diehl SM, Langer P, Samans B, Ramaswamy A, Zielke A, et al. Analysis by cDNA microarrays of gene expression patterns of human adrenocortical tumors. European journal of endocrinology/European Federation of Endocrine Societies 2006;154(4):587–98.PubMedGoogle Scholar
  49. 49.
    Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol 2007.Google Scholar
  50. 50.
    Kim AC, Hammer GD. Adrenocortical cells with stem/progenitor cell properties: recent advances. Mol Cell Endocrinol 2007;265–266:10–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Tissier F, Cavard C, Groussin L, Perlemoine K, Fumey G, Hagnere AM, et al. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 2005;65(17):7622–7.PubMedGoogle Scholar
  52. 52.
    Libe R, Fratticci A, Bertherat J. Adrenocortical cancer: pathophysiology and clinical management. Endocr-Relat Cancer 2007;14(1):13–28.PubMedCrossRefGoogle Scholar
  53. 53.
    Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem 2006;281(32):22429–33.PubMedCrossRefGoogle Scholar
  54. 54.
    Gardner EJ. A genetic and clinical study of intestinal polyposis, a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet 1951;3(2):167–76.PubMedGoogle Scholar
  55. 55.
    Mizusaki H, Kawabe K, Mukai T, Ariyoshi E, Kasahara M, Yoshioka H, et al. Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1) gene transcription is regulated by wnt4 in the female developing gonad. Mol Endocrinol Baltimore, Md 2003;17(4):507–19.Google Scholar
  56. 56.
    Gummow BM, Winnay JN, Hammer GD. Convergence of Wnt signaling and steroidogenic factor-1 (SF-1) on transcription of the rat inhibin alpha gene. J Biol Chem 2003;278(29):26572–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Cellular & Molecular Biology Graduate ProgramUniversity of MichiganAnn ArborUSA
  2. 2.Department of Internal Medicine, Division of Metabolism, Endocrinology and DiabetesUniversity of MichiganAnn ArborUSA

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