Clinical and Molecular Characteristics of PRKACA L206R Mutant Cortisol-Producing Adenomas in Korean Patients.
Adrenocortical adenomas
Cushing syndrome
Gene expression profiling
PRKACA mutation
Wnt signaling pathway
Journal
Endocrinology and metabolism (Seoul, Korea)
ISSN: 2093-5978
Titre abrégé: Endocrinol Metab (Seoul)
Pays: Korea (South)
ID NLM: 101554139
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
30
07
2021
accepted:
14
10
2021
pubmed:
3
12
2021
medline:
16
3
2022
entrez:
2
12
2021
Statut:
ppublish
Résumé
An activating mutation (c.617A>C/p.Lys206Arg, L206R) in protein kinase cAMP-activated catalytic subunit alpha (PRKACA) has been reported in 35% to 65% of cases of cortisol-producing adenomas (CPAs). We aimed to compare the clinical characteristics and transcriptome analysis between PRKACA L206R mutants and wild-type CPAs in Korea. We included 57 subjects with CPAs who underwent adrenalectomy at Seoul National University Hospital. Sanger sequencing for PRKACA was conducted in 57 CPA tumor tissues. RNA sequencing was performed in 13 fresh-frozen tumor tissues. The prevalence of the PRKACA L206R mutation was 51% (29/57). The mean age of the study subjects was 42±12 years, and 87.7% (50/57) of the patients were female. Subjects with PRKACA L206R mutant CPAs showed smaller adenoma size (3.3±0.7 cm vs. 3.8±1.2 cm, P=0.059) and lower dehydroepiandrosterone sulfate levels (218±180 ng/mL vs. 1,511±3,307 ng/mL, P=0.001) than those with PRKACA wild-type CPAs. Transcriptome profiling identified 244 differentially expressed genes (DEGs) between PRKACA L206R mutant (n=8) and wild-type CPAs (n=5), including five upregulated and 239 downregulated genes in PRKACA L206R mutant CPAs (|fold change| ≥2, P<0.05). Among the upstream regulators of DEGs, CTNNB1 was the most significant transcription regulator. In several pathway analyses, the Wnt signaling pathway was downregulated and the steroid biosynthesis pathway was upregulated in PRKACA mutants. Protein-protein interaction analysis also showed that PRKACA downregulates Wnt signaling and upregulates steroid biosynthesis. The PRKACA L206R mutation in CPAs causes high hormonal activity with a limited proliferative capacity, as supported by transcriptome profiling.
Sections du résumé
BACKGROUND
An activating mutation (c.617A>C/p.Lys206Arg, L206R) in protein kinase cAMP-activated catalytic subunit alpha (PRKACA) has been reported in 35% to 65% of cases of cortisol-producing adenomas (CPAs). We aimed to compare the clinical characteristics and transcriptome analysis between PRKACA L206R mutants and wild-type CPAs in Korea.
METHODS
We included 57 subjects with CPAs who underwent adrenalectomy at Seoul National University Hospital. Sanger sequencing for PRKACA was conducted in 57 CPA tumor tissues. RNA sequencing was performed in 13 fresh-frozen tumor tissues.
RESULTS
The prevalence of the PRKACA L206R mutation was 51% (29/57). The mean age of the study subjects was 42±12 years, and 87.7% (50/57) of the patients were female. Subjects with PRKACA L206R mutant CPAs showed smaller adenoma size (3.3±0.7 cm vs. 3.8±1.2 cm, P=0.059) and lower dehydroepiandrosterone sulfate levels (218±180 ng/mL vs. 1,511±3,307 ng/mL, P=0.001) than those with PRKACA wild-type CPAs. Transcriptome profiling identified 244 differentially expressed genes (DEGs) between PRKACA L206R mutant (n=8) and wild-type CPAs (n=5), including five upregulated and 239 downregulated genes in PRKACA L206R mutant CPAs (|fold change| ≥2, P<0.05). Among the upstream regulators of DEGs, CTNNB1 was the most significant transcription regulator. In several pathway analyses, the Wnt signaling pathway was downregulated and the steroid biosynthesis pathway was upregulated in PRKACA mutants. Protein-protein interaction analysis also showed that PRKACA downregulates Wnt signaling and upregulates steroid biosynthesis.
CONCLUSION
The PRKACA L206R mutation in CPAs causes high hormonal activity with a limited proliferative capacity, as supported by transcriptome profiling.
Identifiants
pubmed: 34852451
pii: EnM.2021.1217
doi: 10.3803/EnM.2021.1217
pmc: PMC8743585
doi:
Substances chimiques
Protein Kinases
EC 2.7.-
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
EC 2.7.11.11
PRKACA protein, human
EC 2.7.11.11
Hydrocortisone
WI4X0X7BPJ
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1287-1297Références
J Clin Endocrinol Metab. 2011 Apr;96(4):E728-38
pubmed: 21252250
Endocr Rev. 2017 Dec 1;38(6):516-537
pubmed: 28973103
J Clin Endocrinol Metab. 2008 Oct;93(10):4135-40
pubmed: 18647815
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
J Biol Chem. 2006 Apr 14;281(15):9971-6
pubmed: 16476742
Eur J Endocrinol. 2015 Jun;172(6):677-85
pubmed: 25750087
Horm Metab Res. 2017 Apr;49(4):301-306
pubmed: 27871112
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Nat Rev Endocrinol. 2016 May;12(5):255-62
pubmed: 26965378
Endocr J. 2014;61(8):825-32
pubmed: 25069672
J Clin Endocrinol Metab. 2017 Mar 1;102(3):786-792
pubmed: 27797672
Science. 2014 May 23;344(6186):917-20
pubmed: 24855271
Hum Mol Genet. 2010 Apr 15;19(8):1387-98
pubmed: 20080939
Nat Commun. 2014 Dec 05;5:5680
pubmed: 25477193
Endocrinol Metab (Seoul). 2015 Sep;30(3):297-304
pubmed: 26248856
Endocrinology. 2000 Aug;141(8):2895-903
pubmed: 10919277
Bioinformatics. 2014 Feb 15;30(4):523-30
pubmed: 24336805
Mol Cell Biol. 2005 Oct;25(20):9063-72
pubmed: 16199882
N Engl J Med. 1991 Dec 12;325(24):1688-95
pubmed: 1944469
BMC Bioinformatics. 2011 Aug 04;12:323
pubmed: 21816040
Nat Commun. 2016 Sep 14;7:12751
pubmed: 27624192
Nat Genet. 2014 Jun;46(6):613-7
pubmed: 24747643
J Clin Endocrinol Metab. 2014 Oct;99(10):E2093-100
pubmed: 25057884
N Engl J Med. 2014 Mar 13;370(11):1019-28
pubmed: 24571724
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
PLoS One. 2016 Sep 08;11(9):e0162606
pubmed: 27606678
Science. 2014 May 23;344(6186):913-7
pubmed: 24700472
Nat Genet. 2000 Sep;26(1):89-92
pubmed: 10973256
Nucleic Acids Res. 2018 Jan 4;46(D1):D661-D667
pubmed: 29136241
J Clin Endocrinol Metab. 2011 Jan;96(1):E208-14
pubmed: 21047926
Lancet. 2015 Aug 29;386(9996):913-27
pubmed: 26004339