Molecular and immunohistochemical investigation of protein kinase a regulatory subunit type 1A (<i>PRKAR1A</i>) in odontogenic myxomas

Perdigão, Paola F.; Stergiopoulos, Sotirios; Marco, Luiz; Matyakhina, Ludmila; Boikos, Sosipatros A.; Gomez, Ricardo Santiago; Pimenta, Flávio Juliano; Stratakis, Constantine A.

doi:10.1002/gcc.20232

Cited by 33 publications

(23 citation statements)

References 28 publications

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“…14,15 A subset of these tumors (28 melanomas and the 7 PEMs) were microdissected to study normal and tumor tissue DNA for LOH for 9 chromosome 17q22-24 markers and an intragenic PRKAR1A polymorphic sequence (PRKAR1A [CA] n ) in a manner analogous to that reported previously. 2,14,24 The markers were: D17S807, D17S1874, D17S1882, D17S789, PRKAR1A[CA] n , D17S795, D17S2182, D17S940, D17S1295, and D17S1300.…”

Section: Genetic Studiesmentioning

confidence: 99%

“…PRKAR1A is mutated in more than half of CNC patients 14 ; loss of heterozygosity (LOH) can be demonstrated in tumors from CNC patients. 27 Molecular studies also revealed R1a down-regulation, PRKAR1A-inactivating mutations, and/or 17q22-24 LOH in certain sporadic tumors including adrenocortical adenomas, 2 thyroid cancer, 25 and odontogenic myxomas, 24 and in pituitary somatotropic cells in vitro (R1a). 12 Mouse models of R1a down-regulation partially mimic CNC; these animals develop schwannomas, fibroosseous bone lesions, adrenocortical hyperplasia and thyroid adenomas, histiocytic and epithelial neoplasms, lymphomas, and other mesenchymal tumors.…”

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confidence: 97%

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Loss of Expression of Protein Kinase A Regulatory Subunit 1α in Pigmented Epithelioid Melanocytoma But Not in Melanoma or Other Melanocytic Lesions

Zembowicz

Knoepp

Bei³

et al. 2007

American Journal of Surgical Pathology

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114

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Pigmented epithelioid melanocytoma (PEM) is a recently described entity comprising most cases previously described as "animal-type melanoma" and epithelioid blue nevus (EBN) occurring in patients with the multiple neoplasia syndrome Carney complex (CNC). Mutations of the protein kinase A regulatory subunit type 1alpha (R1alpha) (coded by the PRKAR1A gene) are found in more than half of CNC patients. In this study, we investigated whether PEM and EBN are related at the molecular level, and whether changes in the PRKAR1A gene status and the expression of the R1alpha protein may be involved in the pathogenesis of PEM and other melanocytic lesions. Histologic analysis of hematoxylin and eosin-stained sections and immunohistochemistry (IHC) with R1alpha antibody were performed on 34 sporadic PEMs, 8 CNC-associated PEMs from patients with known PRKAR1A mutations, 297 benign and malignant melanocytic tumors (127 conventional sections of 10 compound nevi, 10 Spitz nevi, 5 deep-penetrating nevi, 5 blue nevi, 6 cellular blue nevi, 2 malignant blue nevi, 3 lentigo maligna, and 86 melanomas of various types); in addition, 170 tissue microarray sections consisting of 35 benign nevi, 60 primary melanomas, and 75 metastatic melanomas, and 5 equine dermal melanomas, were examined. Histologic diagnoses were based on preexisting pathologic reports and were confirmed for this study. DNA studies [loss of heterozygosity (LOH) for the 17q22-24 locus and the PRKAR1A gene sequencing] were performed on 60 melanomas and 7 PEMs. IHC showed that R1alpha was expressed in all but one core from tissue microarrays (169/170), and in all 127 melanocytic lesions evaluated in conventional sections. By contrast, R1alpha was not expressed in the 8 EBN from patients with CNC and PRKAR1A mutations. Expression of R1alpha was lost in 28 of 34 PEMs (82%). R1alpha was expressed in the 5 equine melanomas studied. DNA studies correlated with IHC findings: there were no PRKAR1A mutations in any of the melanomas studied and the rate of LOH for 17q22-24 was less than 7%; 5 of the 7 PEMs showed extensive 17q22-24 LOH but no PRKAR1A mutations. The results support the concept that PEM is a distinct melanocytic tumor occurring in a sporadic setting and in the context of CNC. They also suggest that PEM differs from melanomas in equine melanotic disease, further arguing that the term animal-type melanoma may be a misnomer for this group of lesions. Loss of expression of R1alpha offers a useful diagnostic test that helps to distinguish PEM from lesions that mimic it histologically.

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Section: Genetic Studiesmentioning

confidence: 99%

mentioning

confidence: 97%

Loss of Expression of Protein Kinase A Regulatory Subunit 1α in Pigmented Epithelioid Melanocytoma But Not in Melanoma or Other Melanocytic Lesions

Zembowicz

Knoepp

Bei³

et al. 2007

American Journal of Surgical Pathology

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114

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“…Not all of these lesions exhibited consistent losses of the normal R1α allele [33, 34]. In a recent study, screening of sporadic odontogenic myxomas identified mutations of the coding region of PRKAR1A in 2 of them [35]. …”

Section: Prkar1a and Tumorigenesismentioning

confidence: 99%

Carney Complex: Pathology and Molecular Genetics

Boikos

Stratakis²

2006

Neuroendocrinology

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Carney complex (CNC) is a unique multiple endocrine neoplasia syndrome (MIM 160980) which is characterized by unusual biochemical features (chronic hypersomatotropinemia and paradoxical responses of cortisol production to glucocorticoids) and multi-tissue involvement. The gene coding for the protein kinase A (PKA) type 1α regulatory subunit, PRKAR1A, had been mapped to 17q22–24, one of the genetic loci involved in CNC, and allelic analysis using probes from this chromosomal region revealed consistent changes in CNC tumors. Sequencing of the PRKAR1A gene in over 100 kindreds showed a number of mutations; in almost all cases, the sequence change was predicted to lead to a premature stop codon, and mutant mRNAs were subject to nonsense-mediated mRNA decay. In CNC cells, PKA activity assays showed increased stimulation by cAMP. Few mutations that did not lead to a premature stop codon have been described; they are also associated with increased PKA activity. PRKAR1A has been investigated in sporadic endocrine tumors; it does not appear to be mutated in pituitary adenomas, but both thyroid and adrenal neoplasms have been found to harbor somatic mutations of this gene. Animal models of the disease have been developed. CNC is the first human disease caused by mutations of one of the subunits of the PKA holoenzyme, a critical component of numerous cellular signaling systems. This has wide implications for cAMP involvement in endocrine tumorigenesis.

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“…Our research group described mutations of the PRKAR1A gene in OM samples (4). Rearrangements of the HMGA2 gene were also recently reported in OM (23).…”

Section: Discussionmentioning

confidence: 58%

Hypomethylation of tumor suppressor genes in odontogenic myxoma

et al. 2011

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Odontogenic myxoma (OM) is an ectomesenchymal benign odontogenic tumor characterized by spindle or stellate-shaped cells embedded in an abundant myxoid or mucoid extracellular matrix. DNA methylation is characterized by the addition of methyl groups in cytosines within CpG islands in the promoter gene. DNA methylation can decrease the expression of tumor suppressor genes and contribute to the development of neoplastic lesions. The aim of study was to evaluate the methylation pattern of the tumor suppressor genes P16 (CDKN2A), P21 (CDKN1A), P27 (CDKN1B), P53 (TP53) and RB1 in OM and dental pulp. Methylation was evaluated using methylation-specific polymerase chain reaction (PCR). The transcription was studied in some cases by using reverse transcription quantitative PCR. A higher frequency of unmethylated P27, P53, and RB1 samples was observed in the OM when compared with the dental pulp. OM expressed mRNA of all the genes evaluated. Considering all the samples together, the expression of Rb was higher in the unmethylated samples compared with the partially methylated samples. This investigation revealed hypomethylation of the genes P27, P53, and RB1 in OM. In addition, methylation of tumor suppressor genes was found to be an usual event in normal dental pulp.

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Molecular and immunohistochemical investigation of protein kinase a regulatory subunit type 1A (PRKAR1A) in odontogenic myxomas

Cited by 33 publications

References 28 publications

Loss of Expression of Protein Kinase A Regulatory Subunit 1α in Pigmented Epithelioid Melanocytoma But Not in Melanoma or Other Melanocytic Lesions

Loss of Expression of Protein Kinase A Regulatory Subunit 1α in Pigmented Epithelioid Melanocytoma But Not in Melanoma or Other Melanocytic Lesions

Carney Complex: Pathology and Molecular Genetics

Hypomethylation of tumor suppressor genes in odontogenic myxoma

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