The tumor-suppressor gene encoding the
cyclic AMP-dependent protein kinase A type I-alpha regulatory subunit PRKAR1A has been mapped to chromosome 17 (17q22-24) and is mutated in
Carney complex, a familial
neoplasia syndrome that is associated with thyroid
tumors. Other genes implicated in
cyclic nucleotide-dependent signaling have been investigated in thyroid
tumorigenesis. We studied
protein kinase A (PKA) activity in noninherited follicular
thyroid adenomas and follicular, papillary, and undifferentiated (
anaplastic) thyroid carcinomas. We then examined these and additional thyroid
tumors for losses of the 17q22-24 PRKAR1A region, mutations of the PRKAR1A gene, and expression of its
peptide product. Total PKA activity was markedly increased in
carcinomas over that in
adenomas, whereas the ratio of free vs. total PKA activity was decreased in
cancer. Consistent with these findings, the 17q22-24 region was frequently lost in
cancer but not in benign
adenomas. A novel inactivating mutation of the PRKAR1A gene (leading to premature termination of the predicted
protein) was found in an aggressive
thyroid cancer. The
tumor with PRKAR1A gene mutation, as well as the
tumors with 17q allelic losses, showed decreased PRKAR1A expression by immunostaining. We conclude that PRKAR1A, the most abundant regulatory subunit of
protein kinase A and a principal
cyclic AMP-signaling modulator, acts as a tumor-suppressor gene in sporadic
thyroid cancer. Published 2002 Wiley-Liss, Inc.