PRKACA Mutations in Adrenal Adenomas: Genotype/Phenotype Correlations

Abstract

Untargeted, next generation sequencing approaches have provided deep insights into genetic events that result in unopposed steroidogenesis from the adrenal cortex. In particular, somatic mutations in the gene encoding the catalytic subunit α of protein kinase A (PKA) (PRKACA) were identified independently by several groups as the most frequently altered gene in cortisol-producing adenomas. Detailed functional studies could explore the molecular consequences of these hot-spot mutations and large international cohorts have provided the basis to explore the clinical characteristics associated with this mutation. Thereby, PRKACA mutations are highly specific for cortisol over-secretion, while they are absent or very rare in the context of other adrenal diseases. Patients carrying these somatic mutations are affected by a more severe phenotype and are identified at a younger age. Thus, these genotype/phenotype correlations provide further evidence for the importance of PKA-dependent pathways for adrenal physiology and disease.

Key words

adrenal tumor - adrenal cortex - cortisol - Cushing’s syndrome

Publication History

Received: 11 August 2016

Accepted: 26 October 2016

Article published online:
21 November 2016

• References

• 1 Beuschlein F, Fassnacht M, Assié G, Calebiro D, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Reincke M, Bertherat J, Strom TM, Allolio B.. Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome. N Engl J Med 2014; 370: 1019-1028
• 2 Cao Y, He M, Gao Z, Peng Y, Li Y, Li L, Zhou W, Li X, Zhong X, Lei Y, Su T, Wang H, Jiang Y, Yang L, Wei W, Yang X, Jiang X, Liu L, He J, Ye J, Wei Q, Li Y, Wang W, Wang J, Ning G.. Activating hotspot L205R mutation in PRKACA and adrenal Cushing’s syndrome. Science 2014; 344: 913-917
• 3 Sato Y, Maekawa S, Ishii R, Sanada M, Morikawa T, Shiraishi Y, Yoshida K, Nagata Y, Sato-Otsubo A, Yoshizato T, Suzuki H, Shiozawa Y, Kataoka K, Kon A, Aoki K, Chiba K, Tanaka H, Kume H, Miyano S, Fukayama M, Nureki O, Homma Y, Ogawa S.. Recurrent somatic mutations underlie corticotropin-independent Cushing’s syndrome. Science 2014; 344: 917-920
• 4 Goh G, Scholl UI, Healy JM, Choi M, Prasad ML, Nelson-Williams C, Kunstman JW, Korah R, Suttorp A-C, Dietrich D, Haase M, Willenberg HS, Stalberg P, Hellman P, Akerstrom G, Bjorklund P, Carling T, Lifton RP.. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat Genet 2014; 46: 613-617
• 5 Di Dalmazi G, Kisker C, Calebiro D, Mannelli M, Canu L, Arnaldi G, Quinkler M, Rayes N, Tabarin A, Laure Jullié M, Mantero F, Rubin B, Waldmann J, Bartsch DK, Pasquali R, Lohse M, Allolio B, Fassnacht M, Beuschlein F, Reincke M.. Novel Somatic Mutations in the Catalytic Subunit of the Protein Kinase A as a Cause of Adrenal Cushing’s Syndrome: A European Multicentric Study. J Clin Endocrinol Metab 2014; 99: E2093-E2100
• 6 Nakajima Y, Okamura T, Gohko T, Satoh T, Hashimoto K, Shibusawa N, Ozawa A, Ishii S, Tomaru T, Horiguchi K, Okada S, Takata D, Rokutanda N, Horiguchi J, Tsushima Y, Oyama T, Takeyoshi I, Yamada M.. Somatic mutations of the catalytic subunit of cyclic AMP-dependent protein kinase (PRKACA) gene in Japanese patients with several adrenal adenomas secreting cortisol [Rapid Communication]. Endocr J 2014; 61: 825-832
• 7 Thiel A, Reis AC, Haase M, Goh G, Schott M, Willenberg HS, Scholl UI.. PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases. Eur J Endocrinol 2015; 172: 677-685
• 8 Li X, Wang B, Tang L, Lang B, Zhang Y, Zhang F, Chen L, Ouyang J, Zhang X.. Clinical characteristics of PRKACA mutations in Chinese patients with adrenal lesions: a single-centre study. Clin Endocrinol (Oxf). 2016 Jun 14 doi:10.1111/cen.13134 [Epub ahead of print]
• 9 Calebiro D, Hannawacker A, Lyga S, Bathon K, Zabel U, Ronchi C, Beuschlein F, Reincke M, Lorenz K, Allolio B, Kisker C, Fassnacht M, Lohse MJ.. PKA catalytic subunit mutations in adrenocortical Cushing’s adenoma impair association with the regulatory subunit. Nat Commun 2014; 5: 5680
• 10 Ronchi CL, Di Dalmazi G, Faillot S, Sbiera S, Assié G, Weigand I, Calebiro D, Schwarzmayr T, Appenzeller S, Rubin B, Waldmann J, Scaroni C, Bartsch DK, Mantero F, Mannelli M, Kastelan D, Chiodini I, Bertherat J, Reincke M, Strom TM, Fassnacht M, Beuschlein F. ENSAT. Genetic landscape of sporadic unilateral adrenocortical adenomas without PRKACA p.Leu206Arg mutation. J Clin Endocrinol Metab 2016; 101: 3526-3528
• 11 Carney JA, Lyssikatos C, Lodish MB, Stratakis CA.. Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes. Hum Pathol 2015; 46: 40-49
• 12 Lodish MB, Yuan B, Levy I, Braunstein GD, Lyssikatos C, Salpea P, Szarek E, Karageorgiadis AS, Belyavskaya E, Raygada M, Faucz FR, Izatt L, Brain C, Gardner J, Quezado M, Carney JA, Lupski JR, Stratakis CA.. Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations. Eur J Endocrinol 2015; 172: 803-811
• 13 Rosenberg D, Groussin L, Jullian E, Perlemoine K, Bertagna X, Bertherat J. Role of the PKA-regulated transcription factor CREB in development and tumorigenesis of endocrine tissues. Ann N Y Acad Sci 2002; 968: 65-74
• 14 Bertherat J, Groussin L, Sandrini F, Matyakhina L, Bei T, Stergiopoulos S, Papageorgiou T, Bourdeau I, Kirschner LS, Vincent-Dejean C, Perlemoine K, Gicquel C, Bertagna X, Stratakis CA. Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity. Cancer Res 2003; 63: 5308-5319
• 15 Almeida MQ, Harran M, Bimpaki EI, Hsiao HP, Horvath A, Cheadle C, Watkins T, Nesterova M, Stratakis CA. Integrated genomic analysis of nodular tissue in macronodular adrenocortical hyperplasia: progression of tumorigenesis in a disorder associated with multiple benign lesions. J Clin Endocrinol Metab 2011; 96: E728-E738
• 16 Mantovani G, Lania AG, Bondioni S, Peverelli E, Pedroni C, Ferrero S, Pellegrini C, Vicentini L, Arnaldi G, Bosari S, Beck-Peccoz P, Spada A. Different expression of protein kinase A (PKA) regulatory subunits in cortisol-secreting adrenocortical tumors: relationship with cell proliferation. Exp Cell Res 2008; 314: 123-130
• 17 Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93: 1526-1540
• 18 Seidel E, Scholl UI. Intracellular Molecular Differences in Aldosterone- Compared to Cortisol-Secreting Adrenal Cortical Adenomas. Front Endocrinol (Lausanne) 2016; 7: 75
• 19 Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y, Tanaka K, Wieland T, Graf E, Saeger W, Ronchi CL, Allolio B, Buchfelder M, Strom TM, Fassnacht M, Komada M. Mutations in the deubiquitinase gene USP8 cause Cushing's disease. Nat Genet 2015; 47: 31-38
• 20 Perez-Rivas LG, Theodoropoulou M, Ferraù F, Nusser C, Kawaguchi K, Stratakis CA, Faucz FR, Wildemberg LE, Assié G, Beschorner R, Dimopoulou C, Buchfelder M, Popovic V, Berr CM, Tóth M, Ardisasmita AI, Honegger J, Bertherat J, Gadelha MR, Beuschlein F, Stalla G, Komada M, Korbonits M, Reincke M. The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing’s Disease. J Clin Endocrinol Metab 2015; 100: E997-E1004
• 21 Ma ZY, Song ZJ, Chen JH, Wang YF, Li SQ, Zhou LF, Mao Y, Li YM, Hu RG, Zhang ZY, Ye HY, Shen M, Shou XF, Li ZQ, Peng H, Wang QZ, Zhou DZ, Qin XL, Ji J, Zheng J, Chen H, Wang Y, Geng DY, Tang WJ, Fu CW, Shi ZF, Zhang YC, Ye Z, He WQ, Zhang QL, Tang QS, Xie R, Shen JW, Wen ZJ, Zhou J, Wang T, Huang S, Qiu HJ, Qiao ND, Zhang Y, Pan L, Bao WM, Liu YC, Huang CX, Shi YY, Zhao Y. Recurrent gain-of-function USP8 mutations in Cushing’s disease. Cell Res 2015; 25: 306-317
• 22 Hayashi K, Inoshita N, Kawaguchi K, Ibrahim Ardisasmita A, Suzuki H, Fukuhara N, Okada M, Nishioka H, Takeuchi Y, Komada M, Takeshita A, Yamada S. The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing’s disease. Eur J Endocrinol 2016; 174: 213-226
• 23 Cao Y, Gao Z, Li L, Jiang X, Shan A, Cai J, Peng Y, Li Y, Jiang X, Huang X, Wang J, Wei Q, Qin G, Zhao J, Jin X, Liu L, Li Y, Wang W, Wang J, Ning G. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nat Commun 2013; 4: 2810
• 24 Lichtenauer UD, Di Dalmazi G, Slater EP, Wieland T, Kuebart A, Schmittfull A, Schwarzmayr T, Diener S, Wiese D, Thasler WE, Reincke M, Meitinger T, Schott M, Fassnacht M, Bartsch DK, Strom TM, Beuschlein F. Frequency and clinical correlates of somatic Ying Yang 1 mutations in sporadic insulinomas. J Clin Endocrinol Metab 2015; 100: E776-E782
• 25 Cromer MK, Choi M, Nelson-Williams C, Fonseca AL, Kunstman JW, Korah RM, Overton JD, Mane S, Kenney B, Malchoff CD, Stalberg P, Akerström G, Westin G, Hellman P, Carling T, Björklund P, Lifton RP. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas. Proc Natl Acad Sci USA 2015; 112: 4062-4067
• 26 Lee JH, Lee ES, Kim YS. Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid: a meta-analysis. Cancer 2007; 110: 38-46
• 27 Åkerström T, Crona J, Delgado Verdugo A, Starker LF, Cupisti K, Willenberg HS, Knoefel WT, Saeger W, Feller A, Ip J, Soon P, Anlauf M, Alesina PF, Schmid KW, Decaussin M, Levillain P, Wängberg B, Peix JL, Robinson B, Zedenius J, Bäckdahl M, Caramuta S, Iwen KA, Botling J, Stålberg P, Kraimps JL, Dralle H, Hellman P, Sidhu S, Westin G, Lehnert H, Walz MK, Åkerström G, Carling T, Choi M, Lifton RP, Björklund P. Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS One 2012; 7: e41926
• 28 Terzolo M, Osella G, Alì A, Borretta G, Cesario F, Paccotti P, Angeli A. Subclinical Cushing's syndrome in adrenal incidentaloma. Clin Endocrinol (Oxf) 1998; 48: 89-97
• 29 Grossrubatscher E, Vignati F, Possa M, Lohi P. The natural history of incidentally discovered adrenocortical adenomas: a retrospective evaluation. J Endocrinol Invest 2001; 24: 846-855
• 30 Barzon L, Fallo F, Sonino N, Boscaro M. Development of overt Cushing’s syndrome in patients with adrenal incidentaloma. Eur J Endocrinol 2002; 146: 61-66
• 31 Fagour C, Bardet S, Rohmer V, Arimone Y, Lecomte P, Valli N, Tabarin A. Usefulness of adrenal scintigraphy in the follow-up of adrenocortical incidentalomas: a prospective multicenter study. Eur J Endocrinol 2009; 160: 257-264
• 32 Vassilatou E, Vryonidou A, Michalopoulou S, Manolis J, Caratzas J, Phenekos C, Tzavara I. Hormonal activity of adrenal incidentalomas: results from a long-term follow-up study. Clin Endocrinol (Oxf) 2009; 70: 674-679
• 33 Morelli V, Reimondo G, Giordano R, Della Casa S, Policola C, Palmieri S, Salcuni AS, Dolci A, Mendola M, Arosio M, Ambrosi B, Scillitani A, Ghigo E, Beck-Peccoz P, Terzolo M, Chiodini I. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab 2014; 99: 827-834
• 34 Di Dalmazi G, Vicennati V, Garelli S, Casadio E, Rinaldi E, Giampalma E, Mosconi C, Golfieri R, Paccapelo A, Pagotto U, Pasquali R. Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: a 15-year retrospective study. Lancet Diabetes Endocrinol 2014; 2: 396-405
• 35 Späth M, Korovkin S, Antke C, Anlauf M, Willenberg HS. Aldosterone- and cortisol-co-secreting adrenal tumors: the lost subtype of primary aldosteronism. Eur J Endocrinol 2011; 164: 447-455
• 36 Rhayem Y, Gustavo Perez-Rivas L, Dietz A, Bathon K, Gebhard C, Riester A, Mauracher B, Gomez-Sanchez C, Eisenhofer G, Schwarzmayr T, Calebiro D, Strom TM, Reincke M, Beuschlein F. PRKACA somatic mutations are rare findings in aldosterone-producing adenomas. J Clin Endocrinol Metab 2016 in print
• 37 Nanba K, Omata K, Tomlins SA, Giordano TJ, Hammer GD, Rainey WE, Else T. Double adrenocortical adenomas harboring independent KCNJ5 and PRKACA somatic mutations. Eur J Endocrinol 2016; 175: K1-K6