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| {{CMG}}; {{AE}} {{RT}} {{AAM}} {{MAD}} | | {{CMG}}; {{AE}} {{RT}} {{AAM}} {{MAD}} |
| ==Overview== | | ==Overview== |
| There are no established causes for adrenocortical carcinoma. | | There are no established causes for adrenocortical carcinoma. The relatively increased [[incidence]] in childhood is mainly explained by [[germline]] [[TP53 (gene)|TP53]] [[mutations]], which are the underlying [[Genetics|genetic]] cause of ACC in more than 50% to 80% of children. |
| ==Causes== | | ==Causes== |
| *There are no established causes for adrenocortical carcinoma. | | *There are no established causes for adrenocortical carcinoma. |
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| == Genetics == | | == Genetics == |
| The [[Genetics|genetic]] dissection of ACC has revealed [[Genomics|genomic]] aberrations that contribute to [[Neoplastic disease|neoplastic]] transformation of [[Adrenal cortex|adrenocortical]] cells:
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| '''''1. [[Clone (cell biology)|Clonality]]'''''
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| * ACCs initiate from [[Monoclonal|monoclonal cell]] populations, suggesting that [[mutation]] events lead to [[Clonal selection|clonal expansion]] and ultimate progression to [[cancer]].<ref>{{Cite journal
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| | author = [[F. Beuschlein]], [[M. Reincke]], [[M. Karl]], [[W. D. Travis]], [[C. Jaursch-Hancke]], [[S. Abdelhamid]], [[G. P. Chrousos]] & [[B. Allolio]]
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| | title = Clonal composition of human adrenocortical neoplasms
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| | journal = [[Cancer research]]
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| | volume = 54
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| | issue = 18
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| | pages = 4927–4932
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| | year = 1994
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| | month = September
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| | pmid = 7915195
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| }}</ref>
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| * [[Flow cytometry]] revealed [[aneuploidy]] in ACC. [[aneuploidy]] was observed in 75% of ACC.<ref>{{Cite journal
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| | author = [[C. Gicquel]], [[M. Leblond-Francillard]], [[X. Bertagna]], [[A. Louvel]], [[Y. Chapuis]], [[J. P. Luton]], [[F. Girard]] & [[Y. Le Bouc]]
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| | title = Clonal analysis of human adrenocortical carcinomas and secreting adenomas
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| | journal = [[Clinical endocrinology]]
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| | volume = 40
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| | issue = 4
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| | pages = 465–477
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| | year = 1994
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| | month = April
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| | pmid = 7910530
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| }}</ref>
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| * Assessment of [[aneuploidy]] with [[histopathological]] criteria in 7 of 9 [[Adrenal tumor|adrenal tumors]] revealed a high correlation with Weiss score >3 (indicative of [[malignancy]]).<ref>{{Cite journal
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| | author = [[J. B. Amberson]], [[E. D. Jr Vaughan]], [[G. F. Gray]] & [[G. J. Naus]]
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| | title = Flow cytometric determination of nuclear DNA content in benign adrenal pheochromocytomas
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| | journal = [[Urology]]
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| | volume = 30
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| | issue = 2
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| | pages = 102–104
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| | year = 1987
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| | month = August
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| | pmid = 3617290
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| }}</ref>
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| * No significant difference in overall survival was observed in patients with ACC exhibiting [[aneuploidy]] vs patients with ACC exhibiting [[Diploids|diploid]] [[Neoplasm|neoplasms]].<ref>{{Cite journal
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| | author = [[E. S. Cibas]], [[L. J. Medeiros]], [[D. S. Weinberg]], [[A. B. Gelb]] & [[L. M. Weiss]]
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| | title = Cellular DNA profiles of benign and malignant adrenocortical tumors
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| | journal = [[The American journal of surgical pathology]]
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| | volume = 14
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| | issue = 10
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| | pages = 948–955
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| | year = 1990
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| | month = October
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| | pmid = 2403197
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| }}</ref>
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| '''''2. [[Gene expression]] [[DNA microarray|arrays]]'''''
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| * An initial study identified elevated [[Gene expression|expression of genes]] involved in cell proliferation in ACC, such as ''[[IGF2]]'', compared with increased [[Gene expression|expression]] of [[steroidogenic]] [[genes]] in ACA.<ref>{{Cite journal
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| | author = [[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]]
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| | title = Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy
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| | journal = [[The Journal of clinical endocrinology and metabolism]]
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| | volume = 90
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| | issue = 3
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| | pages = 1819–1829
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| | year = 2005
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| | month = March
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| | doi = 10.1210/jc.2004-1075
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| | pmid = 15613424
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| }}</ref>
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| * Giordano et al identified unique [[Transcription (genetics)|transcriptionally]] activated (12q and 5q) and repressed (11q, 1p, and 17p) [[chromosomal]] regions in 33 ACCs vs 22 ACAs in a [[DNA microarray|microarray]] study.<ref>{{Cite journal
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| | author = [[Thomas J. Giordano]], [[Rork Kuick]], [[Tobias Else]], [[Paul G. Gauger]], [[Michelle Vinco]], [[Juliane Bauersfeld]], [[Donita Sanders]], [[Dafydd G. Thomas]], [[Gerard Doherty]] & [[Gary Hammer]]
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| | title = Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling
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| | journal = [[Clinical cancer research : an official journal of the American Association for Cancer Research]]
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| | volume = 15
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| | issue = 2
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| | pages = 668–676
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| | year = 2009
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| | month = January
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| | doi = 10.1158/1078-0432.CCR-08-1067
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| | pmid = 19147773
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| }}</ref>
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| * Giordano et al (192) determined that ACC with high [[histological]] [[Grading (tumors)|grade]] exhibited [[overexpression]] of [[cell cycle]] and functional [[aneuploidy]] [[genes]] and leading to the decreased survival of patients.
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| * Expression levels of ''BUB1B,'' ''[[PINK1]], and [[DLG7]]'' ''are'' identified in ACC.<ref>{{Cite journal
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| | author = [[Aurelien de Reynies]], [[Guillaume Assie]], [[David S. Rickman]], [[Frederique Tissier]], [[Lionel Groussin]], [[Fernande Rene-Corail]], [[Bertrand Dousset]], [[Xavier Bertagna]], [[Eric Clauser]] & [[Jerome Bertherat]]
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| | title = Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival
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| | journal = [[Journal of clinical oncology : official journal of the American Society of Clinical Oncology]]
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| | volume = 27
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| | issue = 7
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| | pages = 1108–1115
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| | year = 2009
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| | month = March
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| | doi = 10.1200/JCO.2008.18.5678
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| | pmid = 19139432
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| }}</ref>
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| ==== 3. '''''[[MicroRNAs]]''''' ====
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| * [[MicroRNAs]] are [[RNA|RNAs]] that are important in the regulation of [[gene expression]].
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| * Numerous [[MicroRNA|miRNAs]] have been identified in the regulation of various [[cellular]] processes such as [[proliferation]], [[Apoptosis|apoptosis,]] and [[differentiation]].<ref>{{Cite journal
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| | author = [[Benjamin Czech]] & [[Gregory J. Hannon]]
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| | title = Small RNA sorting: matchmaking for Argonautes
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| | journal = [[Nature reviews. Genetics]]
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| | volume = 12
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| | issue = 1
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| | pages = 19–31
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| | year = 2011
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| | month = January
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| | doi = 10.1038/nrg2916
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| | pmid = 21116305
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| }}</ref>
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| * Dysregulation of [[Micro-RNA|miRNAs]], such as [[overexpression]] or deletion, plays an important role in diseases.
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| * Mistargeting of the [[Micro-RNA|miRNAs]], resulting in inhibition or activation of various [[oncogenes]], [[Tumor suppressor|tumor suppressors]], and other factors important in [[tumor]] [[Angiogenesis|angiogenesis]].<ref>{{Cite journal
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| | author = [[Amaia Lujambio]] & [[Scott W. Lowe]]
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| | title = The microcosmos of cancer
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| | journal = [[Nature]]
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| | volume = 482
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| | issue = 7385
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| | pages = 347–355
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| | year = 2012
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| | month = February
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| | doi = 10.1038/nature10888
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| | pmid = 22337054
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| }}</ref>
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| * The investigation identified 14 upregulated [[Micro-RNA|miRNAs]] and 9 downregulated [[Micro-RNA|miRNAs]] unique to ACC.<ref>{{Cite journal
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| | author = [[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]]
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| | title = miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer
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| | journal = [[Clinical cancer research : an official journal of the American Association for Cancer Research]]
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| | volume = 15
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| | issue = 24
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| | pages = 7684–7692
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| | year = 2009
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| | month = December
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| | doi = 10.1158/1078-0432.CCR-09-1587
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| | pmid = 19996210
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| }}</ref>
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| * Upregulated [[Micro-RNA|miRNAs]] in ACCs included miR-184, miR-210, and miR-503.
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| * Downregulated miRNAs included miR-214, miR-375, and miR-511.
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| * Levels of miR-184, miR-503, and miR-511 are able to distinguish benign from [[malignant]] [[Adrenal tumor|adrenal tumors]].<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid19546168-16|[16]]]</sup>
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| * MiR-483 was found to be significantly upregulated in pediatric ACCs.
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| * MiR-99a and miR-100 are bioinformatically predicted to target the 3- untranslated regions of ''IGF1R'', ''RPTOR'', and ''FRAP1'' and were experimentally confirmed to target several components of the [[IGF-1]] signaling pathway.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid20484036-17|[17]]]</sup>
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| ==== 4. '''''[[Gene mutation|Gene mutations]]''''' ====
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| * Targeted [[Genetics|genetic]] analyses have identified [[somatic]] [[Genetics|genetic]] changes in ''[[TP53 (gene)|TP53]]'', ''[[MEN1]]'', [[Insulin-like growth factor 2|''IGF2'',]] ''[[IGF2R]]'', and ''[[P16 (gene)|p16]]''.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid11454518-18|[18]]]</sup>
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| * ''[[TP53 (gene)|TP53]]'' located on 17p13 is the most commonly mutated [[gene]] in ACC, present in at least one-third of ACCs.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid22504887-19|[19]]]</sup>
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| * LOH in the [[gene]] encoding [[P16INK4a|p16ink]]/ [[p14arf]], ''[[CDKN2A]]'' 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.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid10022445-20|[20]]]</sup>
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| * ''[[MEN1]]'' [[somatic]] [[mutations]] are unusual in sporadic ACC.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid17854394-21|[21]]]</sup>
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| * The canonical [[Wnt signaling pathway|Wnt pathway]], the [[Catenin|catenin gene]], and ''CTNNB1'' have been identified as activating point mutations in over 25% of both ACAs and ACCs in children and adults.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid18647815-22|[22]]]</sup>
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| ==== 5. '''''[[Chromosomal aberration|Chromosomal aberrations]]''''' ====
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| * [[Comparative genomic hybridization]]([[Comparative genomic hybridization|CGH]]) can identify structural [[chromosomal]] abnormalities within ACCs.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid23093492-23|[23]]]</sup>
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| * ACCs showed complex [[chromosomal]] alterations. ACCs contained multiple [[chromosomal]] gains or losses with a mean of 10 events.
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| * The newest study confirmed increased alterations in ACC (44%) compared with ACAs (10%).
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| * In ACCs, the frequently observed [[chromosomal]] gains at 5, 7, 12, 16, 19, and 20 and losses at 13 and 22 were confirmed.
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| * The group identified genes within these regions with potential tumorigenic potential including [[Fibroblast growth factor|fibroblast growth factor 4]] (''[[FGF4]]''), [[cyclin-dependent kinase 4]] (''[[CDK4]]''), and [[cyclin E1]]([[CCNE1|''CCNE1'')]]. The study confirmed the diagnostic utility of 6 [[loci]] (5q, 7p, 11p, 13q, 16q, and 22q) in the differentiation of ACA and ACC.
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| * [[Genomic]] aberration at [[chromosomes]] 5, 12, and 17 are predicted to illustrate [[genes]] that initiate or maintain [[Neoplasm|neoplastic]] transformation. [[Chromosome]] 17, specifically at 17p13, contains the well-known [[tumor suppressor gene]] ''[[TP53 (gene)|TP53]]''.
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| === 6. '''''[[Epigenetics|Epigenetic]]''''' ===
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| * [[DNA methylation]] involves the addition of a [[methyl group]] to the [[cytosine]] [[pyrimidine]] ring or [[adenine]] [[purine]] ring.<sup>[[Adrenocortical carcinoma pathophysiology#cite note-pmid25111790-24|[24]]]</sup>
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| * Dysregulation in this process is observed in [[Tumor cell|tumor cells.]]
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| * A recent study revealed [[Methylation|hypermethylation]] of promoters in ACC with correlation to poor survival and identified ''[[H19 (gene)|H19]]'', ''[[PLAGL1]]'', ''[[G0 phase|G0S2]]'', and ''[[NDRG2]]'' as silenced genes also provided evidence about the role of [[methylation]] in ACC [[tumorigenesis]], particularly in the 11p15 [[locus]] containing ''[[IGF2]]'' and ''[[H19 (gene)|H19]]''.
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| === Hereditary syndromes associated with adrenocortical carcinoma are: === | | === Hereditary syndromes associated with adrenocortical carcinoma are: === |
| * [[Lynch syndrome]] | | * [[Lynch syndrome]] |