Pituitary adenomas: a pathway to understanding the aggressive form. Clinical genetic analysis of potential prognostic markers in the development of aggressive pituitary adenomas

BACKGROUND. Currently, due to the lack of clear criteria for predicting the aggressive course of pituitary adenomas (APA), the search for diagnostic markers is highly relevant. Genetic markers, among others, may serve as such markers since their identification is possible at early stages of the pathological process.

OBJECTIVE. To study the prevalence of genotypic polymorphisms G634C of the VEGFA gene (locus rs2010963), C/T of the TP53_2 gene (locus rs17884159), C/T of the HIF1A gene (locus rs11549465), and G-197A of the IL-17A gene in a sample of patients with APA and their association with the development of various clinical variants of the aggressive course of the disease.

MATERIALS AND METHODS. The study included 100 patients with a clinically confirmed diagnosis of pituitary adenoma (main group) and 83 practically healthy individuals (control group). The polymorphism of the studied genes was analyzed using allele-specific polymerase chain reaction (PCR) with SNP-Express reagent kits in real-time mode ("Sintol", Russia). The interpretation of the results was carried out using the "RotorGene" software of the PCR-RV device. The study also included general clinical, biochemical, and hormonal tests, as well as instrumental and neuroimaging methods, including magnetic resonance imaging (MRI) of the chiasmatic-sellar region and statistical analysis.

RESULTS. The study showed that the heterozygous mutation (G/C) of the G634C VEGFA polymorphism was recorded in 21 cases (26%), and the homozygous mutation with a complete replacement of guanine (G) by cysteine (C) at position 634 (C/C) was detected in 4 cases. In patients with invasive pituitary adenomas (PA), the heterozygous variant (G/C) was twice as frequent — 32.7% (n=17) compared to the control group — 15.7% (n=13). The homozygous genotype (C/C) was also more frequently observed in patients with invasive PA growth — 7.7% (n=4) compared to the control group.

The heterozygous variant (C/T) of the HIF1A gene was significantly more common (p=0.02) in patients with invasive adenomas compared to the control group: 25% (n=13) and 9.8% (n=8), respectively. In non-invasive PAs, this genotype was observed three times less frequently. The study of TP53_2 polymorphism (locus rs17884159) showed that in patients with invasive PAs, the frequency of the heterozygous variant (C/T) was significantly higher — 15.4% (n=8) compared to the control group — 4.8% (n=4).

CONCLUSION. The conducted genetic analysis of polymorphisms in the VEGFA, HIF1A, TP53_2, and IL-17A genes revealed significant deviations, confirming their practical significance in the early diagnosis of aggressive pituitary adenomas.

1. Molitch ME. Diagnosis and Treatment of Pituitary Adenomas: A Review. JAMA. 2017;317(5):516-524. doi: https://doi.org/10.1001/jama.2016.19699

2. Melmed S, Kaiser UB, Lopes MB, et al. Clinical Biology of the Pituitary Adenoma. Endocr Rev. 2022;43(6):1003-1037. doi: https://doi.org/10.1210/endrev/bnac010

3. Molitch ME. Diagnosis and Treatment of Pituitary Adenomas: A Review. JAMA. 2017;317(5):516-524. doi: https://doi.org/10.1001/jama.2016.19699

4. Dekkers OM, Karavitaki N, Pereira AM. The epidemiology of aggressive pituitary tumors (and its challenges). Rev Endocr Metab Disord. 2020;21(2):209-212. doi: https://doi.org/10.1007/s11154-020-09556-7

5. Lania AG, Ferrero S, Pivonello R, et al. Evolution of an aggressive prolactinoma into a growth hormone secreting pituitary tumor coincident with GNAS gene mutation. J Clin Endocrinol Metab. 2010;95(1):13-17. doi: https://doi.org/10.1210/jc.2009-1360

6. Raverot G, Burman P, McCormack A, et al. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol. 2018;178(1):G1-G24. doi: https://doi.org/10.1530/EJE-17-0796

7. Burman P, Casar-Borota O, Perez-Rivas LG, Dekkers OM. Aggressive Pituitary Tumors and Pituitary Carcinomas: From Pathology to Treatment. J Clin Endocrinol Metab. 2023;108(7):1585-1601. doi: https://doi.org/10.1210/clinem/dgad098

8. McCormack A, Dekkers OM, Petersenn S, et al. Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. Eur J Endocrinol. 2018;178(3):265-276. doi: https://doi.org/10.1530/EJE-17-0933

9. Burman P, Trouillas J, Losa M, et al. Aggressive pituitary tumours and carcinomas, characteristics and management of 171 patients. Eur J Endocrinol. 2022;187(4):593-605. doi: https://doi.org/10.1530/EJE-22-0440

10. Trouillas J, Roy P, Sturm N, et al. A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathol. 2013;126(1):123-135. doi: https://doi.org/10.1007/s00401-013-1084-y

11. Langlois F, Lim DST, Yedinak CG, et al. Predictors of silent corticotroph adenoma recurrence; a large retrospective single center study and systematic literature review. Pituitary. 2018;21(1):32-40. doi: https://doi.org/10.1007/s11102-017-0844-4

12. Manojlovic-Gacic E, Bollerslev J, Casar-Borota O. Invited Review: Pathology of pituitary neuroendocrine tumours: present status, modern diagnostic approach, controversies and future perspectives from a neuropathological and clinical standpoint. Neuropathol Appl Neurobiol. 2020;46(2):89-110. doi: https://doi.org/10.1111/nan.12568

13. Perez-Rivas LG, Simon J, Albani A, et al. TP53 mutations in functional corticotroph tumors are linked to invasion and worse clinical outcome. Acta Neuropathol Commun. 2022;10(1):139. doi: https://doi.org/10.1186/s40478-022-01437-1

14. Neou M, Villa C, Armignacco R, et al. Pangenomic Classification of Pituitary Neuroendocrine Tumors. Cancer Cell. 2020;37(1):123-134.e5. doi: https://doi.org/10.1016/j.ccell.2019.11.002

15. Smith TR, Lobo M, Maltenfort M, et al. VEGFA polymorphisms and their role in aggressive pituitary adenomas: A systematic review. J Clin Endocrinol Metab. 2019;104(4):1357-1365. doi: https://doi.org/10.1210/jc.2018-01824

16. Gonzalez B, Fernandez R, Martinez G, et al. TP53 gene polymorphisms and their association with pituitary adenoma progression. Oncol Rep. 2021;45(3):1089-1096. doi: https://doi.org/10.3892/or.2021.7983

17. Zhang X, Wang W, Wei H, et al. HIF1A polymorphism and its potential impact on hypoxia-induced tumor progression in pituitary adenomas. Mol Med Rep. 2020;21(2):689-697. doi: https://doi.org/10.3892/mmr.2020.10962

18. Lee YJ, Park HJ, Kim J, et al. The role of IL-17A in therapy-resistant pituitary tumors: A potential biomarker for aggressive adenomas. Endocr Relat Cancer. 2021;28(5):379-389. doi: https://doi.org/10.1530/ERC-20-0453