Sporadic cardiac myxomas and tumors from patients with Carney complex are not associated with activating mutations of the Gsα gene

Abstract

Cardiac myxomas are rare tumors that may be encountered sporadically or in the context of the Carney complex. The molecular basis for the development of cardiac myxomas and Carney complex tumors is unclear. Pathological myocardial function and myocardial hypertrophy have been associated with alterations in the heterotrimeric GTP-binding proteins. The postulated proto-oncogenic character of the gene encoding the alpha sub-unit of the stimulatory GTP-binding protein Gs alpha (gsp) in pituitary and thyroid tumors, the finding of identical somatic gsp mutations in the myocardium of patients with McCune-Albright syndrome, and the associated endocrine anomalies of the Carney complex prompted us to investigate the occurrence of activating missense mutations in the Gs alpha gene in 10 sporadically occurring atrial myxomas and in 8 tumors from 7 patients with Carney complex. No gsp mutations could be demonstrated by using the polymerase chain reaction and denaturing gradient gel electrophoresis complemented by direct DNA sequencing. Thus, activating Gs alpha mutations neither are associated with the development of atrial myxomas, nor can be demonstrated in other tumors from patients with Carney complex. The significance of these mutations in the myocardium of asymptomatic patients with McCune-Albright syndrome remains to be determined.

Pituitary Pathology in Carney Complex Patients

“…The pattern of biochemical abnormalities of GH and PRL secretion without pituitary tumors that are detectable by common imaging modalities, and infrequent development of clinically significant acromegaly is reminiscent of the situation in McCune-Albright syndrome (MAS) [13][14][15][16]. Studies of tumors excised from patients with CNC had indicated that their molecular abnormality may be in the molecular pathway that involves the stimulatory α-subunit of the guanine nucleotide-binding protein (Gsα) [17,18], GNAS-the gene responsible for MAS [13]. However, Gsα mutations were not present in an investigation of a series of CNC tumors [18].…”

“…Studies of tumors excised from patients with CNC had indicated that their molecular abnormality may be in the molecular pathway that involves the stimulatory α-subunit of the guanine nucleotide-binding protein (Gsα) [17,18], GNAS-the gene responsible for MAS [13]. However, Gsα mutations were not present in an investigation of a series of CNC tumors [18].…”

Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice

“…We examined this by injecting immunodeficient athymic nude mice subcutaneously (s.c.) with Wt, Prkar1a fl/fl , Prkar1a À / À , Bim À / À ; Prkar1a fl/fl or Bim À / ;Prkar1a À / À MEFs. Although MEFs in which Prkar1a had been deleted failed to form tumours in nude mice, combined loss of Prkar1a and Bim rapidly caused readily detectable subcutaneous tumours in 100% recipients (750 mm 3 in approximately four weeks when the mice had to be culled according to ethics guidelines; Figures 2a and b). As additional controls, none of the nude mice injected with Wt, Prkar1a fl/fl or Bim À / À MEFs developed tumours.…”

“…2 Carney complex disease shares similarities with the McCune-Albright syndrome (MAS), particularly paradoxical responses to endocrine signals; accordingly, mutations of genes involved in cyclic nucleotide (e.g., cAMP, cGMP) mediated signalling are implicated in both syndromes. 3 Notably, two thirds of patients with Carney complex syndrome have heterozygous mutations in the Prkar1a gene (chromosome 17q24), which encodes the regulatory subunit RIa (PRKAR1a) of cAMP-dependent protein kinase A (PKA). PRKAR1a protein insufficiency leads to lack of regulation with consequent overactivation of the PKA signalling pathway.…”

Genetics of Carney complex and related familial lentiginoses, and other multiple tumor syndromes

“…These changes did not include the CNC locus on chromosome 2p16, a finding that suggests that alterations of the heterozygosity of the responsible gene(s) are not necessary for oncogenesis in this condition; rather, a gainof-function mutation is more likely. Although mutations of the gsp proto-oncogene were not present in Carney complex tumors (98), and the locations of several genes that code for components of the guanine nucleotide-binding proteins (G-proteins) were excluded by linkage analysis (10,99), it seems likely that the gene or genes responsible for this condition participate in G-protein -controlled orrelated signaling systems.…”