Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas

Abstract

Purpose

somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been described in patients with Cushing’s disease (CD). The aim of the study is to verify whether USP8 mutation may predict early and late outcome of pituitary surgery in patients with CD operated at a single institution.

Methods

We performed a retrospective genetic analysis of 92 adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Specimens were screened for USP8 hotspot mutations in the exon 14 with Sanger sequencing. Hormonal and surgical data were compared between USP8 variant carriers and wild-type tumors.

Results

USP8 variants were detected in 22 adenomas (23.9%) with higher prevalence in women (28.9% vs. 5.3% in men; p < 0.05). No significant difference in hormonal levels and tumoral features in relation to USP8 status was observed. Interestingly, USP8-variant carriers were more likely to achieve surgical remission than wild-type adenomas (100% vs. 75.7%; p = 0.01). Conversely, recurrence of CD occurred in 23% of USP8-mutated patients and in 13% of patients with wild-type adenoma. The recurrence-free survival did not differ significantly between the two groups (p = 0.42).

Conclusions

ACTH-secreting pituitary adenomas carrying somatic USP8 mutations are associated with a greater likelihood of surgical remission in patients operated by a single neurosurgeon. Recurrence rates are not related with USP8-variant status.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    O.M. Dekkers, E. Horvath-Puho, J.O. Jørgensen, S.C. Cannegieter, V. Ehrenstein, J.P. Vandenbroucke et al. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J. Clin. Endocrinol. Metab. 98, 2277–2284 (2013)

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    L.K. Nieman, B.M. Biller, J.W. Findling, M.H. Murad, J. Newell-Price, M.O. Savage et al. Treatment of Cushing’s syndrome: An Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 100, 2807–2831 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    D. Bochicchio, M. Losa, M. Buchfelder, Factors influencing the immediate and late outcome of Cushing’s disease treated by transsphenoidal surgery: a retrospective study by the European Cushing’s Disease Survey Group. J. Clin. Endocrinol. Metab. 80, 3114–3120 (1995)

    CAS  PubMed  Google Scholar 

  4. 4.

    B.M. Hofman, M. Hlavac, R. Martinez, M. Buchfelder, O.A. Muller, R. Fahlbusch, Long-term results after microsurgery for Cushing’s disease: experience with 426 primary operations over 35 years. J. Neurosurg. 108, 9–18 (2008)

    Article  Google Scholar 

  5. 5.

    W.F. Chandler, A.L. Barkan, T. Hollon, A. Sakharova, J. Sack, B. Brahma et al. Outcome of transsphenoidal surgery for Cushing disease: a single–center experience over 32 years. Neurosurgery 78, 216–223 (2016)

    Article  PubMed  Google Scholar 

  6. 6.

    R. Pivonello, M. De Leo, A. Cozzolino, A. Colao, The treatment of Cushing’s disease. Endocr. Rev. 36, 385–486 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    M. Losa, R. Bianchi, R. Barzaghi, M. Giovanelli, P. Mortini, Persistent ACTH response to desmopressin in the early postoperative period is a risk factor for recurrence of Cushing’s disease. J. Clin. Endocrinol. Metab. 94, 3322–3328 (2009)

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    S. Melmed, Pathogenesis of pituitary tumors. Nat. Rev. Endocrinol. 7, 257–266 (2011)

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    S. Sbiera, T. Deutschbein, I. Weigand, M. Reincke, M. Fassnacht, B. Allolio, The new molecular landscape of Cushing’s disease. Trends Endocrinol. Metab. 26, 573–583 (2015)

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    C.A. Stratakis, Diagnosis and clinical genetics of Cushing syndrome in pediatrics. Endocrinol. Metab. Clin. North. Am. 45, 311–328 (2016)

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    A. Albani, M. Theodoropoulou, M. Reincke, Genetics of Cushing’s disease. Clin. Endocrinol. (Oxf.). 88, 3–12 (2018)

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Z.Y. Ma, Z.J. Song, J.H. Chen, Y.F. Wang, S.Q. Li, L.F. Zhou et al. Recurrent gain-of-function USP8 mutations in Cushing’s disease. Cell Res. 25, 306–317 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    M. Reincke, S. Sbiera, A. Hayakawa, M. Theodoropoulou, A. Osswald, F. Beuschlein et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat. Genet. 47, 31–38 (2015)

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    L.G. Pérez-Rivas, M. Theodoropoulou, F. Ferraù, C. Nusser, K. Kawaguchi, C.A. Stratakis et al. The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing’s disease. J. Clin. Endocrinol. Metab. 100, E997–E1004 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    K. Hayashi, N. Inoshita, K. Kawaguchi, A. Ibrahim Ardisasmita, H. Suzuki, N. Fukuhara et al. The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing’s disease. Eur. J. Endocrinol. 174, 213–226 (2016)

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    F.R. Faucz, A. Tirosh, C. Tatsi, A. Berthon, L.C. Hernandez-Ramirez, N. Settas et al. Somatic USP8 gene mutations are a common cause of pediatric Cushing disease. J. Clin. Endocrinol. Metab. 102, 2836–2843 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    M. Theodoropoulou, T. Arzberger, Y. Gruebler, M.L. Jaffrain-Rea, J. Schlegel, L. Schaaf et al. Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells. J. Endocrinol. 183, 385–394 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    H. Fukuoka, O. Cooper, A. Ben-Shlomo, A. Mamelak, S.G. Ren, D. Bruyette et al. EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J. Clin. Invest. 121, 4712–4721 (2011)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    M. Losa, P. Mortini, S. Dylgjeri, R. Barzaghi, A. Franzin, C. Mandelli et al. Desmopressin stimulation test before and after pituitary surgery in patients with Cushing’s disease. Clin. Endocrinol. (Oxf.). 55, 61–68 (2001)

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    M.F. Cassarino, A.G. Ambrogio, A. Cassarino, M.R. Terreni, D. Gentilini, A. Sesta et al. Gene expression profiling in human corticotrope tumors reveals distinct, neuroendocrine profiles. J. Neuroendocrinol. 30, e12628 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    M.F. Cassarino, A. Sesta, L. Pagliardini, M. Losa, G. Lasio, F. Cavagnini et al. Proopiomelanocortin, glucocorticoid, and CRH receptor expression in human ACTH-secreting pituitary adenomas. Endocrine 55, 853–860 (2017)

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    F. Pecori Giraldi, L. Pagliardini, M.F. Cassarino, M. Losa, G. Lasio, F. Cavagnini, Responses to corticotrophin-releasing hormone and dexamethasone in a large series of human adrenocorticotrophic hormone-secreting pituitary adenomas in vitro reveal manifold corticotroph tumoural phenotypes. J. Neuroendocrinol. 23, 1214–1221 (2011)

    Article  CAS  PubMed  Google Scholar 

  23. 23.

    M. Ravo, M. Mutarelli, L. Ferraro, O.M. Grober, O. Paris, R. Tarallo et al. Quantitative expression profiling of highly degraded RNA from formalin-fixed, paraffin-embedded breast tumor biopsies by oligonucleotide microarrays. Lab. Invest. 88, 430–440 (2008)

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    C. Ballmann, A. Thiel, H.E. Korah, A.C. Reis, W. Saeger, S. Stepanow et al. USP8 mutations in pituitary Cushing adenomas – targeted analysis by next-generation sequencing. J. Endocr. Soc. 2, 266–278 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    L.G. Pérez-Rivas, M. Theodoropoulou, T.H. Puar, J. Fazel, M.R. Stieg, F. Ferraù et al. Somatic USP8 mutations are frequent events in corticotroph tumor progression causing Nelson’s tumor. Eur. J. Endocrinol. 178, 59–65 (2018)

    Article  Google Scholar 

  26. 26.

    A., Albani, L.G., Pérez-Rivas, C., Dimopoulou, S., Zopp, P., Colon-Bolea, S., Roeber, et al. The USP8 mutational status may predict long-term remission in patients with Cushing’s disease. Clin. Endocrinol. (Oxf). (2018). https://doi.org/10.1111/cen.13802

  27. 27.

    S.S. Chaidarun, B. Swearingen, J.M. Alexander, Differential expression of estrogen receptor-ß (ER ß) in human pituitary tumors: functional interactions with ER α and a tumor-specific splice variant. J. Clin. Endocrinol. Metab. 83, 3308–3315 (1998)

    CAS  PubMed  Google Scholar 

  28. 28.

    S. Oomizu, J. Honda, S. Takeuchi, T. Kakeya, T. Masui, S. Takahashi, Transforming growth factor-α stimulates proliferation of mammotrophs and corticotrophs in the mouse pituitary. J. Endocrinol. 165, 493–501 (2000)

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    F.F. Casanueva, A.L. Barkan, M. Buchfelder, A. Klibanski, E.R. Laws, J.S. Loeffler et al. Criteria for the definition of pituitary tumor centers of excellence (PTCOE): a Pituitary Society statement. Pituitary 20, 489–498 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research did not receive any specific grant from any agency in the public, commercial or not-for-profit sector.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Marco Losa.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Losa, M., Mortini, P., Pagnano, A. et al. Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas. Endocrine 63, 240–246 (2019). https://doi.org/10.1007/s12020-018-1776-0

Download citation

Keywords

  • Pituitary neoplasms
  • Pituitary surgery
  • Adrenocorticotropin
  • Cortisol