Abstract 4417: Molecular Mechanisms of PRKAR1A-Dependent Cardiac Tumorigenesis
Cardiac myxomas are the most common primary heart tumors and can occur in Carney complex (CNC), a familial neoplasia syndrome of recurrent cardiac and extracardiac myxomas, endocrinopathy, and spotty skin pigmentation. We previously showed that haploinsufficient mutations of the PRKAR1A gene, encoding the R1a subunit of the Protein Kinase A (PKA), cause CNC in ~2/3 of affected individuals. To define genetic mechanisms underlying CNC tumorigenesis, we established primary tumor cell lines from 20 cardiac myxomas resected from 17 different CNC patients. Genomic DNA from tumor cells and matched lymphoblastoid lines were used in mutational analyses of PRKAR1A as well as of PRKACA, the gene encoding Ca (the most widely expressed PKA catalytic subunit). 16 myxomas exhibited at least 1 mutant PRKAR1A allele, and 6 of these 16 had no constitutional mutation but exhibited somatic mutation of both PRKAR1A alleles. Of 10 tumors with PRKAR1A constitutional mutations, 5 showed PRKAR1A loss of heterozygosity (LOH), and these findings highlighted the significance but not uniformity of this event during tumorigenesis. However, in 1 cardiac myxoma with a PRKAR1A constitutional mutation but without LOH, we identified a somatic PRKACA mutation: IVS7–12ins(C). This mutation disrupts PRKACA mRNA splicing. Resultant encoded mutant protein has no PKA enzymatic activity but does tightly bind to and sequester R1a protein. Thus, the PRKACA mutation diminishes the R1a:Ca ratio and thereby mimics the effects of PRKAR1A LOH leading to cardiac tumorigenesis. We therefore hypothesized that augmentation of the R1a:Ca ratio might rescue the CNC tumorigenic phenotype. To test this model, we bred prkar1a +/−, prkaca +/+ mice into a prkaca +− background to increase the R1a:Ca ratio. Although 65% of prkar1a +/−, prkaca +/+ mice develop tumors, we observed that only 19% of prkar1a +/−, prkaca +/− compound heterozygotes developed tumors, an ~3.5 fold decrease in tumorigenesis. Therefore, we demonstrate that genetic aberrations which alter the R1a:Ca ratio represent a key mechanism underlying Carney complex tumorigenesis. Further studies targeting the modification of Ca expression to alter the R1a:Ca ratio may provide a novel therapeutic platform for patients with cardiac myxomas.