![]() Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors. PKA activity induces cortisol production and cell proliferation 11, 12, 13, 14, 15, providing a mechanism for tumor development. Leu206Arg PRKACA loses PRKAR1A binding, increasing the phosphorylation of downstream targets. Leu206 directly interacts with the regulatory subunit of PKA, PRKAR1A 9, 10. PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Further sequencing identified this mutation in 13 of 63 tumors (35% of adenomas with overt Cushing's syndrome). Six others had somatic mutations in PRKACA (protein kinase A (PKA) catalytic subunit) resulting in a p.Leu206Arg substitution. Six of these had known gain-of-function mutations in CTNNB1 (β-catenin) 5, 6 or GNAS (Gα s) 7, 8. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Eight tumors (including three carcinomas) had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Adrenal tumors autonomously producing cortisol cause Cushing's syndrome 1, 2, 3, 4. ![]()
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