Adrenocortical carcinoma causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]Ahmad Al Maradni, M.D. [3]

Overview

There are no established causes for adrenocortical carcinoma.

Causes

  • There are no established causes for Adrenocortical carcinoma.
  • The relatively increased incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in >50% to 80% of children.

Genetics

The genetic dissection of ACC has revealed genomic aberrations that contribute to neoplastic transformation of adrenocortical cells:

1. Clonality

2. Gene expression arrays

  • Expression levels of BUB1B, PINK1, and DLG7 are identified in ACC.[7]

3. MicroRNAs

  • MicroRNAs are RNAs that are important in the regulation of gene expression.
  • Numerous miRNAs have been identified in the regulation of various cellular processes such as proliferationapoptosis, and differentiation.[8]
  • Dysregulation of miRNAs, such as overexpression or deletion, plays an important role in diseases.
  • Mistargeting of the miRNAs, resulting in inhibition or activation of various oncogenestumor suppressors, and other factors important in tumor angiogenesis.[9]
  • The investigation identified 14 upregulated miRNAs and 9 downregulated miRNAs unique to ACC.[10]
  • Upregulated miRNAs in ACCs included miR-184, miR-210, and miR-503.
  • Downregulated miRNAs included miR-214, miR-375, and miR-511.
  • Levels of miR-184, miR-503, and miR-511 are able to distinguish benign from malignant adrenal tumors.[16]
  • MiR-483 was found to be significantly upregulated in pediatric ACCs.
  • MiR-99a and miR-100 are bioinformatically predicted to target the 3- untranslated regions of IGF1RRPTOR, and FRAP1 and were experimentally confirmed to target several components of the IGF-1 signaling pathway.[17]

4. Gene mutations

  • TP53 located on 17p13 is the most commonly mutated gene in ACC, present in at least one-third of ACCs.[19]
  • LOH in the gene encoding p16inkp14arfCDKN2A is observed in a subset of ACCs. The tumor suppressor function of this gene has been established in multiple cancers. LOH of 11q13 has been identified in 83% of samples.[20]
  • MEN1 somatic mutations are unusual in sporadic ACC.[21]
  • The canonical Wnt pathway, the catenin gene, and CTNNB1 have been identified as activating point mutations in over 25% of both ACAs and ACCs in children and adults.[22]

5. Chromosomal aberrations

  • ACCs showed complex chromosomal alterations. ACCs contained multiple chromosomal gains or losses with a mean of 10 events.
  • The newest study confirmed increased alterations in ACC (44%) compared with ACAs (10%).
  • In ACCs, the frequently observed chromosomal gains at 5, 7, 12, 16, 19, and 20 and losses at 13 and 22 were confirmed.

6. Epigenetic

Hereditary syndromes associated with adrenocortical carcinoma are:

Differential Diagnosis Gene mutations Clinical picture
Lynch syndrome
Neurofibromatosis type 1
MEN1[11]
  • MENIN
Carney complex
BWS[12]

References

  1. F. Beuschlein, M. Reincke, M. Karl, W. D. Travis, C. Jaursch-Hancke, S. Abdelhamid, G. P. Chrousos & B. Allolio (1994). "Clonal composition of human adrenocortical neoplasms". Cancer research. 54 (18): 4927–4932. PMID 7915195. Unknown parameter |month= ignored (help)
  2. C. Gicquel, M. Leblond-Francillard, X. Bertagna, A. Louvel, Y. Chapuis, J. P. Luton, F. Girard & Y. Le Bouc (1994). "Clonal analysis of human adrenocortical carcinomas and secreting adenomas". Clinical endocrinology. 40 (4): 465–477. PMID 7910530. Unknown parameter |month= ignored (help)
  3. J. B. Amberson, E. D. Jr Vaughan, G. F. Gray & G. J. Naus (1987). "Flow cytometric determination of nuclear DNA content in benign adrenal pheochromocytomas". Urology. 30 (2): 102–104. PMID 3617290. Unknown parameter |month= ignored (help)
  4. E. S. Cibas, L. J. Medeiros, D. S. Weinberg, A. B. Gelb & L. M. Weiss (1990). "Cellular DNA profiles of benign and malignant adrenocortical tumors". The American journal of surgical pathology. 14 (10): 948–955. PMID 2403197. Unknown parameter |month= ignored (help)
  5. Florence de Fraipont, Michelle El Atifi, Nadia Cherradi, Gwennaelle Le Moigne, Genevieve Defaye, Remi Houlgatte, Jerome Bertherat, Xavier Bertagna, Pierre-Francois Plouin, Eric Baudin, Francois Berger, Christine Gicquel, Olivier Chabre & Jean-Jacques Feige (2005). "Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy". The Journal of clinical endocrinology and metabolism. 90 (3): 1819–1829. doi:10.1210/jc.2004-1075. PMID 15613424. Unknown parameter |month= ignored (help)
  6. Thomas J. Giordano, Rork Kuick, Tobias Else, Paul G. Gauger, Michelle Vinco, Juliane Bauersfeld, Donita Sanders, Dafydd G. Thomas, Gerard Doherty & Gary Hammer (2009). "Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling". Clinical cancer research : an official journal of the American Association for Cancer Research. 15 (2): 668–676. doi:10.1158/1078-0432.CCR-08-1067. PMID 19147773. Unknown parameter |month= ignored (help)
  7. Aurelien de Reynies, Guillaume Assie, David S. Rickman, Frederique Tissier, Lionel Groussin, Fernande Rene-Corail, Bertrand Dousset, Xavier Bertagna, Eric Clauser & Jerome Bertherat (2009). "Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival". Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 27 (7): 1108–1115. doi:10.1200/JCO.2008.18.5678. PMID 19139432. Unknown parameter |month= ignored (help)
  8. Benjamin Czech & Gregory J. Hannon (2011). "Small RNA sorting: matchmaking for Argonautes". Nature reviews. Genetics. 12 (1): 19–31. doi:10.1038/nrg2916. PMID 21116305. Unknown parameter |month= ignored (help)
  9. Amaia Lujambio & Scott W. Lowe (2012). "The microcosmos of cancer". Nature. 482 (7385): 347–355. doi:10.1038/nature10888. PMID 22337054. Unknown parameter |month= ignored (help)
  10. Patsy Siok Hwa Soon, Lyndal J. Tacon, Anthony J. Gill, Christopher P. Bambach, Mark S. Sywak, Peter R. Campbell, Michael W. Yeh, Steven G. Wong, Roderick J. Clifton-Bligh, Bruce G. Robinson & Stan B. Sidhu (2009). "miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer". Clinical cancer research : an official journal of the American Association for Cancer Research. 15 (24): 7684–7692. doi:10.1158/1078-0432.CCR-09-1587. PMID 19996210. Unknown parameter |month= ignored (help)
  11. B. Gatta-Cherifi, O. Chabre, A. Murat, P. Niccoli, C. Cardot-Bauters, V. Rohmer, J. Young, B. Delemer, H. Du Boullay, M. F. Verger, J. M. Kuhn, J. L. Sadoul, Ph Ruszniewski, A. Beckers, M. Monsaingeon, E. Baudin, P. Goudet & A. Tabarin (2012). "Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database". European journal of endocrinology. 166 (2): 269–279. doi:10.1530/EJE-11-0679. PMID 22084155. Unknown parameter |month= ignored (help)
  12. H. Segers, R. Kersseboom, M. Alders, R. Pieters, A. Wagner & M. M. van den Heuvel-Eibrink (2012). "Frequency of WT1 and 11p15 constitutional aberrations and phenotypic correlation in childhood Wilms tumour patients". European journal of cancer (Oxford, England : 1990). 48 (17): 3249–3256. doi:10.1016/j.ejca.2012.06.008. PMID 22796116. Unknown parameter |month= ignored (help)

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