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| ==Overview== | | ==Overview== |
| Most [[Adrenocortical carcinoma|adrenocortical carcinomas]] are sporadic, but some occur as a component of hereditary [[cancer]] [[syndromes]] such as [[Li-Fraumeni syndrome]], [[Beckwith-Wiedemann syndrome]], and [[Multiple endocrine neoplasia type 1]]([[MEN1]]). Genetic basis of sporadic incidentaloma includes ''[[TP53 (gene)|TP53]]'' [[gene]]. 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. 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]]. | | Most [[Adrenocortical carcinoma|adrenocortical carcinomas]] are sporadic, but some occur as a component of hereditary [[cancer]] [[syndromes]] such as [[Li-Fraumeni syndrome]], [[Beckwith-Wiedemann syndrome]], and [[Multiple endocrine neoplasia type 1]]([[MEN1]]). |
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| ==Risk Factors== | | ==Risk Factors== |
| Most [[Adrenocortical carcinoma|adrenocortical carcinomas]] are sporadic, but some occur as a component of hereditary [[cancer]] [[syndromes]].<ref name="pmid14685087">{{cite journal| author=Sidhu S, Sywak M, Robinson B, Delbridge L| title=Adrenocortical cancer: recent clinical and molecular advances. | journal=Curr Opin Oncol | year= 2004 | volume= 16 | issue= 1 | pages= 13-8 | pmid=14685087 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14685087 }}</ref> | | Most [[Adrenocortical carcinoma|adrenocortical carcinomas]] are sporadic, but some occur as a component of hereditary [[cancer]] [[syndromes]].<ref name="pmid14685087">{{cite journal| author=Sidhu S, Sywak M, Robinson B, Delbridge L| title=Adrenocortical cancer: recent clinical and molecular advances. | journal=Curr Opin Oncol | year= 2004 | volume= 16 | issue= 1 | pages= 13-8 | pmid=14685087 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14685087 }}</ref><ref name="pmid2300390">{{cite journal| author=Lynch HT, Radford B, Lynch JF| title=SBLA syndrome revisited. | journal=Oncology | year= 1990 | volume= 47 | issue= 1 | pages= 75-9 | pmid=2300390 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2300390 }}</ref> |
| * [[Heredity|Hereditary]] [[cancer]] [[syndromes]]:
| | * [[Heredity|Hereditary]] [[cancer]] [[syndromes]]: |
| | | ** [[Li-Fraumeni syndrome]] (associated with inactivating [[Mutation|mutations]] of the ''[[TP53 (gene)|TP53]]'' [[tumor suppressor gene]] on chromosome 17p): |
| * [[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.
| | ***[[Breast cancer]] |
| * [[Beckwith-Wiedemann syndrome]]: [[Wilms' tumor]][[Neuroblastoma|, neuroblastoma]], [[hepatoblastoma]], associated with abnormalities in 11p15
| | *** Soft tissue and [[bone sarcoma]] |
| * [[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 in the [[MEN1|''MEN1'' gene]] on chromosome 11q.<ref name="pmid2300390">{{cite journal| author=Lynch HT, Radford B, Lynch JF| title=SBLA syndrome revisited. | journal=Oncology | year= 1990 | volume= 47 | issue= 1 | pages= 75-9 | pmid=2300390 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2300390 }}</ref>
| | ***[[Brain tumors]] |
| | | ** [[Beckwith-Wiedemann syndrome]] (associated with abnormalities in 11p15): |
| == Genetic basis of risk factors ==
| | ***[[Wilms' tumor]][[Neuroblastoma| Neuroblastoma]] |
| | | ***[[Hepatoblastoma]] |
| ==== Sporadic cases genetics ====
| | **[[Multiple endocrine neoplasia type 1]] ([[MEN1]]) (associated with inactivating mutations of the [[MEN1|''MEN1'' gene]] on [[chromosome]] 11q): |
| * ''[[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> | | ***[[Parathyroid adenoma|Parathyroid adenoma]] |
| * Although the [[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]].<ref name="pmid17289876">{{cite journal| author=Libè R, Groussin L, Tissier F, Elie C, René-Corail F, Fratticci A et al.| title=Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity. | journal=Clin Cancer Res | year= 2007 | volume= 13 | issue= 3 | pages= 844-50 | pmid=17289876 | doi=10.1158/1078-0432.CCR-06-2085 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17289876 }}</ref> | | *** [[Pituitary adenoma|Pituitary adenoma]] |
| * 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. | | ***[[Pancreatic neuroendocrine tumor|Pancreatic neuroendocrine tumors]] and [[Adrenal adenoma|adrenal adenomas]], as well as [[Carcinoma|carcinomas]] |
| 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.]]<ref name="pmid10634406">{{cite journal| author=Bourcigaux N, Gaston V, Logié A, Bertagna X, Le Bouc Y, Gicquel C| title=High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors. | journal=J Clin Endocrinol Metab | year= 2000 | volume= 85 | issue= 1 | pages= 322-30 | pmid=10634406 | doi=10.1210/jcem.85.1.6303 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10634406 }}</ref>
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| [[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]] [[Adrenal tumor|adrenocortical tumors]].<ref name="pmid22471738">{{cite journal| author=Mazzuco TL, Durand J, Chapman A, Crespigio J, Bourdeau I| title=Genetic aspects of adrenocortical tumours and hyperplasias. | journal=Clin Endocrinol (Oxf) | year= 2012 | volume= 77 | issue= 1 | pages= 1-10 | pmid=22471738 | doi=10.1111/j.1365-2265.2012.04403.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22471738 }}</ref> | |
| * 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]].<ref name="pmid11156460">{{cite journal| author=Smith TG, Clark SK, Katz DE, Reznek RH, Phillips RK| title=Adrenal masses are associated with familial adenomatous polyposis. | journal=Dis Colon Rectum | year= 2000 | volume= 43 | issue= 12 | pages= 1739-42 | pmid=11156460 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11156460 }}</ref> | |
| * 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.<ref name="pmid12824913">{{cite journal| author=Kikuchi A| title=Tumor formation by genetic mutations in the components of the Wnt signaling pathway. | journal=Cancer Sci | year= 2003 | volume= 94 | issue= 3 | pages= 225-9 | pmid=12824913 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12824913 }}</ref>
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| Aberrant [[Receptor (biochemistry)|receptors]]
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| * [[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]].
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| [[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]].
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| * In additional reports, the same [[mutation]] was found in over 50 percent of patients with [[Cushing's syndrome]] due to [[Adrenal adenoma|adrenal adenomas]].<ref name="pmid24571724">{{cite journal| author=Beuschlein F, Fassnacht M, Assié G, Calebiro D, Stratakis CA, Osswald A et al.| title=Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. | journal=N Engl J Med | year= 2014 | volume= 370 | issue= 11 | pages= 1019-28 | pmid=24571724 | doi=10.1056/NEJMoa1310359 | pmc=4727447 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24571724 }}</ref> | |
| * 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.<ref name="pmid27389594">{{cite journal| author=Ronchi CL, Di Dalmazi G, Faillot S, Sbiera S, Assié G, Weigand I et al.| title=Genetic Landscape of Sporadic Unilateral Adrenocortical Adenomas Without PRKACA p.Leu206Arg Mutation. | journal=J Clin Endocrinol Metab | year= 2016 | volume= 101 | issue= 9 | pages= 3526-38 | pmid=27389594 | doi=10.1210/jc.2016-1586 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27389594 }}</ref> | |
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| ==== Mutations in [[aldosterone]]-producing adenomas (APA) ====
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| * The most frequent causes of primary [[Hyperaldosteronism|aldosteronism]] include bilateral idiopathic [[hyperplasia]] and unilateral aldosterone-producing adenoma.<ref name="pmid25958045">{{cite journal| author=Monticone S, Castellano I, Versace K, Lucatello B, Veglio F, Gomez-Sanchez CE et al.| title=Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas. | journal=Mol Cell Endocrinol | year= 2015 | volume= 411 | issue= | pages= 146-54 | pmid=25958045 | doi=10.1016/j.mce.2015.04.022 | pmc=4474471 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25958045 }}</ref> | |
| * Somatic [[mutations]] in ''[[KCNJ5]]'' have been identified in patients with primary [[Hyperaldosteronism|aldosteronism]] due to APA.
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| * These [[mutation]]<nowiki/>s are more common in women than men; APAs with ''[[KCNJ5]]'' [[mutations]] are larger than those without [[mutation]]<nowiki/>s.
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| * Somatic [[mutations]] in other important [[genes]] implicated in the regulation of [[aldosterone]] synthesis [[ATP1A1|(''ATP1A1'']]'', [[ATP2B3]], CACNA1D'', ''CTNNB1'', ''ARMC5'') have also been identified.
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| ==References== | | ==References== |