Corticotrophin-releasing hormone (CRH) stimulation test is used in the differential diagnosis of Cushings syndrome. Cushings disease tumours carry somatic driver activating mutations in the ubiquitin-specific-protease 8 (USP8) gene in almost half of the cases. The aim of the present study was to examine whether the USP8 mutational status in Cushings disease tumours influences the response to the CRH stimulation test. We did a monocentric, retrospective study on 46 (27 female) Cushings disease patients with complete data after dynamic stimulation test with 100 μg i.v. CRH (basal serum cortisol and/or ACTH levels and their respective peak and percentage increase). The USP8 mutational status was determined by Sanger sequencing on DNA extracted from fresh frozen and formalin fixed paraffin embedded tumour tissues. USP8 mutations were detected in 22 out of 46 tumours (15/27 female and 7/19 male, chi-square test P=0.245). Mean basal serum cortisol and ACTH levels were similar in patients with USP8 mutant and wild type tumours (μg/dl 24.2±9.5 vs 26.5±11.2, t-test P=0.47 and pg/ml 70.49±53.36 vs 89.46±62.08, P=0.97). Similarly, no significant differences were observed in the cortisol and ACTH peaks after CRH injection between USP8 mutant vs wild type (cortisol μg/dl 38.13±14.02 vs 36.81±16.08, t-test P=0.78 and ACTH pg/ml 164.90±118 vs 179.41±162.2, P=0.73). The percentage increase in cortisol and ACTH levels were higher in patients with USP8 mutant tumours (% cortisol 65.82±48.46 vs 41.57±29.46 and ACTH 201.10±259.74 vs 98.59±86.97) even if they did not reach statistical significance (t-test P=0.053 and P=0.097 respectively). Multivariant analysis showed that patient gender does not influence the response to the CRH stimulation test (P=0.336 and P=0.546 for cortisol and ACTH variation respectively). These data suggest that USP8 mutant tumours may be more sensitive to the CRH stimulation test. This observation together with previously published reports of smaller tumour size and better response to high dose (8 mg) dexamethasone stimulation test (1) highlights the role of USP8 in corticotroph cell physiology.
Reference: 1. Perez-Rivas et al., J Clin Endocrinol Metab, 2015, 100(7):E997E1004.
18 - 21 May 2019
European Society of Endocrinology