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{{CMG}}; {{AE}} | {{CMG}}; {{AE}} | ||
==Overview== | ==Overview== | ||
==Risk Factors== | |||
*Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4]. | |||
Most [[Adrenocortical carcinoma|adrenocortical carcinomas]] are sporadic, but some occur as a component of hereditary [[cancer]] [[syndromes]].<sup>[[Incidentaloma pathophysiology#cite note-pmid14685087-3|[3]]]</sup> | |||
* [[Heredity|Hereditary]] [[cancer]] [[syndromes]]: | |||
* [[Li-Fraumeni syndrome]]: [[breast cancer]], soft tissue and [[bone sarcoma]], [[brain tumors]], associated with inactivating mutations of the ''[[TP53 (gene)|TP53]]'' [[tumor suppressor gene]] on chromosome 17p. | |||
* [[Beckwith-Wiedemann syndrome]]: [[Wilms' tumor]][[Neuroblastoma|, neuroblastoma]], [[hepatoblastoma]], associated with abnormalities in 11p15 | |||
* [[Multiple endocrine neoplasia type 1]] ([[MEN1]]) ([[Parathyroid gland|parathyroid]], [[Pituitary gland|pituitary]], and [[Pancreatic neuroendocrine tumor|pancreatic neuroendocrine tumors]] and [[Adrenal adenoma|adrenal adenomas]], as well as [[Carcinoma|carcinomas]], associated with inactivating mutations of the [[MEN1|''MEN1'' gene]] on chromosome 11q.<sup>[[Incidentaloma pathophysiology#cite note-pmid2300390-10|[10]]]</sup> | |||
== Genetics == | |||
==== Sporadic cases genetics ==== | |||
* ''[[TP53 (gene)|TP53]]'' [[gene]], located on [[chromosome]] 17p13, is the most frequently mutated [[gene]] in human [[cancers]]. A role for the ''[[TP53 (gene)|TP53]]'' [[tumor suppressor gene]] in sporadic ACCs is suggested by the frequent finding of [[loss of heterozygosity]] (LOH) at the 17p13 locus in sporadic ACCs.<sup>[[Incidentaloma pathophysiology#cite note-pmid11559548-11|[11]]]</sup> | |||
* Although [[loss of heterozygosity]] at 17p13 is common, only approximately one-third of these [[tumors]] have a [[mutation]] of ''[[TP53 (gene)|TP53]]''. This suggests that another as yet unidentified suppressor gene is present in this [[locus]].<sup>[[Incidentaloma pathophysiology#cite note-pmid17289876-12|[12]]]</sup> | |||
* Another [[chromosomal]] [[locus]] that is strongly implicated in the pathogenesis of ACC is 11p, the area of abnormality in [[Beckwith-Wiedemann syndrome]] and the site of the [[Insulin-like growth factor 2|insulin-like growth factor-2]] (IGF-2) [[gene]]. LOH at the 11p15 locus and overexpression of [[IGF2|IGF-2]] have been associated with the [[malignant]] [[phenotype]] in sporadic ACCs.<sup>[[Incidentaloma pathophysiology#cite note-pmid9253334-13|[13]]]</sup> However, other growth-related [[Tumor suppressor genes|tumor suppressor gene]]<nowiki/>s at this [[locus]] may also be involved.<sup>[[Incidentaloma pathophysiology#cite note-pmid10634406-14|[14]]]</sup> | |||
Most adrenocortical tumors are [[Monoclonal antibody|monoclonal]], suggesting that they result from accumulated genetic abnormalities, such as activation of [[Oncogenes|proto-oncogenes]] and inactivation of [[Tumor suppressor genes|tumor suppressor genes.]] | |||
[[Beta-catenin]] [[mutations]] (CTNNB1) | |||
* Constitutive activation of [[beta-catenin]] in the Wnt [[signaling pathway]] has been identified as a frequent alteration in [[benign]] and [[malignant]] adrenocortical tumors<sup>[[Incidentaloma pathophysiology#cite note-pmid22471738-15|[15]]]</sup>. | |||
* | * The increased occurrence of [[Adrenal gland|adrenal]] [[tumors]] in patients with [[mutations]] of [[adenomatous polyposis coli]] ([[APC]]) suggested that the Wnt/[[beta-catenin]] pathway could be involved in [[Adrenal gland|adrenal]] [[tumorigenesis]].<sup>[[Incidentaloma pathophysiology#cite note-pmid11156460-16|[16]]]</sup> | ||
* This pathway is essential for [[embryonic]] development of the [[Adrenal gland|adrenal]], and its [[ectopic]] constitutive activation is associated with [[cancer]] development in a number of tissues.<sup>[[Incidentaloma pathophysiology#cite note-pmid12824913-17|[17]]]</sup> | |||
* | Aberrant receptors | ||
* | * [[Cortisol]] hypersecretion is the most frequent [[Hormone|hormonal]] abnormality detected in patients with functioning unilateral [[Adrenal adenoma|adrenal adenomas]]. It had been assumed that the mechanism for this was non-[[Adrenocorticotropic hormone|ACTH]]-dependent autonomous [[cortisol]] secretion from the [[adenoma]]. | ||
[[Somatic]] [[mutations]] of [[protein kinase A]] (PKA) [[Catalysis|catalytic]] subunit (''PRKACA'') were identified in patients with overt [[Cushing's syndrome]] but not in [[adenomas]] secreting less [[cortisol]].<sup>[[Incidentaloma pathophysiology#cite note-pmid24571724-18|[18]]]</sup> | |||
* | * In additional reports, the same [[mutation]] was found in over 50 percent of patients with [[Cushing's syndrome]] due to [[Adrenal adenoma|adrenal adenomas]].<sup>[[Incidentaloma pathophysiology#cite note-pmid27389594-19|[19]]]</sup> | ||
* | * The most frequent hotspot p.Leu206Arg [[mutation]] is located in the active cleft of the [[catalytic]] subunit, inactivating the site where the regulatory subunit RII-beta usually binds, thus causing a constitutive [[Protein kinase A|PKA]] activation. | ||
=== | ==== Mutations in [[aldosterone]]-producing adenomas<sup>[[Incidentaloma pathophysiology#cite note-pmid25958045-20|[20]]]</sup> ==== | ||
* | * The most frequent causes of primary [[Hyperaldosteronism|aldosteronism]] include bilateral idiopathic [[hyperplasia]] and unilateral aldosterone-producing adenoma. | ||
* | * Somatic [[mutations]] in ''[[KCNJ5]]'' have been identified in patients with primary [[Hyperaldosteronism|aldosteronism]] due to APAs. | ||
* | * These [[mutation]]<nowiki/>s are more common in women than men; APAs with ''[[KCNJ5]]'' [[mutations]] are larger than those without [[mutation]]<nowiki/>s. | ||
* | * Somatic [[mutations]] in other important [[genes]] implicated in regulation of [[aldosterone]] synthesis [[ATP1A1|(''ATP1A1'']]'', [[ATP2B3]], CACNA1D'', ''CTNNB1'', ''ARMC5'') have also been identified. | ||
==References== | ==References== | ||
Revision as of 20:33, 25 September 2017
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Risk Factors
- Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].
Most adrenocortical carcinomas are sporadic, but some occur as a component of hereditary cancer syndromes.[3]
- Li-Fraumeni syndrome: breast cancer, soft tissue and bone sarcoma, brain tumors, associated with inactivating mutations of the TP53 tumor suppressor gene on chromosome 17p.
- Beckwith-Wiedemann syndrome: Wilms' tumor, neuroblastoma, hepatoblastoma, associated with abnormalities in 11p15
- Multiple endocrine neoplasia type 1 (MEN1) (parathyroid, pituitary, and pancreatic neuroendocrine tumors and adrenal adenomas, as well as carcinomas, associated with inactivating mutations of the MEN1 gene on chromosome 11q.[10]
Genetics
Sporadic cases genetics
- TP53 gene, located on chromosome 17p13, is the most frequently mutated gene in human cancers. A role for the TP53 tumor suppressor gene in sporadic ACCs is suggested by the frequent finding of loss of heterozygosity (LOH) at the 17p13 locus in sporadic ACCs.[11]
- Although loss of heterozygosity at 17p13 is common, only approximately one-third of these tumors have a mutation of TP53. This suggests that another as yet unidentified suppressor gene is present in this locus.[12]
- Another chromosomal locus that is strongly implicated in the pathogenesis of ACC is 11p, the area of abnormality in Beckwith-Wiedemann syndrome and the site of the insulin-like growth factor-2 (IGF-2) gene. LOH at the 11p15 locus and overexpression of IGF-2 have been associated with the malignant phenotype in sporadic ACCs.[13] However, other growth-related tumor suppressor genes at this locus may also be involved.[14]
Most adrenocortical tumors are monoclonal, suggesting that they result from accumulated genetic abnormalities, such as activation of proto-oncogenes and inactivation of tumor suppressor genes.
Beta-catenin mutations (CTNNB1)
- Constitutive activation of beta-catenin in the Wnt signaling pathway has been identified as a frequent alteration in benign and malignant adrenocortical tumors[15].
- The increased occurrence of adrenal tumors in patients with mutations of adenomatous polyposis coli (APC) suggested that the Wnt/beta-catenin pathway could be involved in adrenal tumorigenesis.[16]
- This pathway is essential for embryonic development of the adrenal, and its ectopic constitutive activation is associated with cancer development in a number of tissues.[17]
Aberrant receptors
- Cortisol hypersecretion is the most frequent hormonal abnormality detected in patients with functioning unilateral adrenal adenomas. It had been assumed that the mechanism for this was non-ACTH-dependent autonomous cortisol secretion from the adenoma.
Somatic mutations of protein kinase A (PKA) catalytic subunit (PRKACA) were identified in patients with overt Cushing's syndrome but not in adenomas secreting less cortisol.[18]
- In additional reports, the same mutation was found in over 50 percent of patients with Cushing's syndrome due to adrenal adenomas.[19]
- The most frequent hotspot p.Leu206Arg mutation is located in the active cleft of the catalytic subunit, inactivating the site where the regulatory subunit RII-beta usually binds, thus causing a constitutive PKA activation.
Mutations in aldosterone-producing adenomas[20]
- The most frequent causes of primary aldosteronism include bilateral idiopathic hyperplasia and unilateral aldosterone-producing adenoma.
- Somatic mutations in KCNJ5 have been identified in patients with primary aldosteronism due to APAs.
- These mutations are more common in women than men; APAs with KCNJ5 mutations are larger than those without mutations.
- Somatic mutations in other important genes implicated in regulation of aldosterone synthesis (ATP1A1, ATP2B3, CACNA1D, CTNNB1, ARMC5) have also been identified.