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Entity | Carney complex syndrome, type I |
Disease | A multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, psammomatous melanotic schwannomas and some other tumors. |
Prognosis | According to the severity of the disease in a given patient, and to the quality of a regular follow up; life span is decreased in patients with CNC. 57% of the deaths are due to heart related causes; others due to the postoperative complications or evolution of the malignant process; presymptomatic diagnosis improves survival data and might prevent earlier the main causes of death in this disease. |
Cytogenetics | Limited data; some of myxomas and PPNAD from CNC patients showed telomeric associations, dicentric chromosomes, aneuploidy, polyploidy and chromosomal rearrangements. |
Hybrid/Mutated Gene | Half of CNC patients show PRKARIA mutations. |
Oncogenesis | PRKARIA is frequently affected by bi-allelic inactivation in tumors of CNC patients. However 1 kindred was described where a splice site mutation led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent PKA signaling at the nuclear level. Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggested that alteration of PRKAR1A function, not only its complete loss, is sufficient for augmenting PKA activity leading to tumorigenesis in tissues in patients with CNC. |
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Entity | PPNAD - Primary pigmented nodular adrenocortical disease Primary pigmented nodular adrenocortical disease |
Disease | PPNAD is a cause of ACTH-independent Cushing's syndrome. This condition can be difficult to diagnose because hypercortisolism may be periodic and adrenal imaging may not demonstrate an adrenal tumor. |
Hybrid/Mutated Gene | Inactivating PRKAR1A germline mutations are frequent in sporadic and isolated cases of PPNAD. |
Oncogenesis | Both alleles are frequently inactivated. The wild-type allele can be inactivated by somatic mutations, consistent with the hypothesis of the gene being a tumor suppressor gene. |
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Entity | Adrenocortical tumors, sporadic |
Disease | Patients frequently present with ACTH-independent Cushing's syndrome. |
Hybrid/Mutated Gene | Somatic mutations in the PRKAR1A gene were identified in 3 cases of sporadic adrenocortical tumor. All 3 mutations predicted premature termination of the protein. 17q23-24 loss-of-heterozygosity is a frequent event in adrenal carcinomas. |
Oncogenesis | Haploinsufficiency of PRKARIA and a reversal of the ratio of R1A to R2B have been proposed to cause tumorigenesis, at least in some cases. |
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Entity | Myxoma, intracardiac |
Disease | Benign neoplasms that occur in 7 per 10,000 individuals. These slowely proliferating lesions arise from subendocardial pluripotent primitive mesenchymal cells, which can differentiate within myxomas along a variety of lineages including epithelial, hematopoietic, and muscular. |
Prognosis | Life span is decreased in patients with myxomas. Morbidity and mortality are the result of embolic stroke, heart failure due to intracardiac obstruction, and rheumatologic symptoms attributed to myxoma-mediated production of IL-6. |
Cytogenetics | Limited data; 15 cases of myxomas contained clonal numerical and structural abnormalities including telomeric associations. |
Hybrid/Mutated Gene | Mutations of PRKARIA detected in the coding region of the gene, exons 5, 7 and 8. |
Oncogenesis | No somatic mutations were detected in cardiac myxomas; haploinsufficiency of PRKARIA and a reversal of the ratio of RIA to R2B have been proposed may contribute in tumorigenesis. |
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Entity | Papillary thyroid carcinoma |
Cytogenetics | Reciprocal translocation between chromosomes 10 and 17 |
Hybrid/Mutated Gene | RET/PTC2 is formed by the fusion of the RET tyrosine kinase domain with part of the RI-alpha regulatory subunit |
Abnormal Protein | RET/PTC2 |
Oncogenesis | The fusion of the RET tyrosine kinase domain with a portion of the RIA gene leads to the expression of RET in the thyroid cells, where it is normally transcriptionally silent. |
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Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity. |
Bertherat J, Groussin L, Sandrini F, Matyakhina L, Bei T, Stergiopoulos S, Papageorgiou T, Bourdeau I, Kirschner LS, Vincent-Dejean C, Perlemoine K, Gicquel C, Bertagna X, Stratakis CA |
Cancer research. 2003 ; 63 (17) : 5308-5319. |
PMID 14500362 |
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Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas. |
Bongarzone I, Butti MG, Coronelli S, Borrello MG, Santoro M, Mondellini P, Pilotti S, Fusco A, Della Porta G, Pierotti MA |
Cancer research. 1994 ; 54 (11) : 2979-2985. |
PMID 8187085 |
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The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-dependent protein kinase. |
Boshart M, Weih F, Nichols M, Schütz G |
Cell. 1991 ; 66 (5) : 849-859. |
PMID 1832337 |
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Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. |
Casey M, Mah C, Merliss AD, Kirschner LS, Taymans SE, Denio AE, Korf B, Irvine AD, Hughes A, Carney JA, Stratakis CA, Basson CT |
Circulation. 1998 ; 98 (23) : 2560-2566. |
PMID 9843463 |
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Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. |
Casey M, Vaughan CJ, He J, Hatcher CJ, Winter JM, Weremowicz S, Montgomery K, Kucherlapati R, Morton CC, Basson CT |
The Journal of clinical investigation. 2000 ; 106 (5) : R31-R38. |
PMID 10974026 |
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Genetic testing and genetic counselling in hypertrophic cardiomyopathy: the French experience. |
Charron P, Héron D, Gargiulo M, Richard P, Dubourg O, Desnos M, Bouhour JB, Feingold J, Carrier L, Hainque B, Schwartz K, Komajda M |
Journal of medical genetics. 2002 ; 39 (10) : 741-746. |
PMID 12362031 |
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Perspective: lessons learned from molecular genetic studies of thyroid cancer--insights into pathogenesis and tumor-specific therapeutic targets. |
Fagin JA |
Endocrinology. 2002 ; 143 (6) : 2025-2028. |
PMID 12021165 |
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PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. |
Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, Della Porta G, Fusco A, Vecchio G |
Cell. 1990 ; 60 (4) : 557-563. |
PMID 2406025 |
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Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. |
Groussin L, Kirschner LS, Vincent-Dejean C, Perlemoine K, Jullian E, Delemer B, Zacharieva S, Pignatelli D, Carney JA, Luton JP, Bertagna X, Stratakis CA, Bertherat J |
American journal of human genetics. 2002 ; 71 (6) : 1433-1442. |
PMID 12424709 |
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Subtractive hybridization cloning of a tissue-specific extinguisher: TSE1 encodes a regulatory subunit of protein kinase A. |
Jones KW, Shapero MH, Chevrette M, Fournier RE |
Cell. 1991 ; 66 (5) : 861-872. |
PMID 1889088 |
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Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. |
Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA |
Nature genetics. 2000 ; 26 (1) : 89-92. |
PMID 10973256 |
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High prevalence of RET proto-oncogene activation (RET/PTC) in papillary thyroid carcinomas. |
Lam KY, Lo CY, Leung PS |
European journal of endocrinology / European Federation of Endocrine Societies. 2002 ; 147 (6) : 741-745. |
PMID 12457448 |
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RET/PTC and RET tyrosine kinase expression in adult papillary thyroid carcinomas. |
Learoyd DL, Messina M, Zedenius J, Guinea AI, Delbridge LW, Robinson BG |
The Journal of clinical endocrinology and metabolism. 1998 ; 83 (10) : 3631-3635. |
PMID 9768676 |
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Regulatory subunit type I-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer. |
Sandrini F, Matyakhina L, Sarlis NJ, Kirschner LS, Farmakidis C, Gimm O, Stratakis CA |
Genes, chromosomes & cancer. 2002 ; 35 (2) : 182-192. |
PMID 12203783 |
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Molecular mechanisms of RET activation in human cancer. |
Santoro M, Melillo RM, Carlomagno F, Fusco A, Vecchio G |
Annals of the New York Academy of Sciences. 2002 ; 963 : 116-121. |
PMID 12095936 |
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