SDHx mutations are associated with the PI3K-Akt signaling pathway in vagal paragangliomas

Anastasiya Snezhkina; Maria  Fedorova; Asiya  Ayupova; Elena  Pudova; Anastasiya  Kobelyatskaya; Dmitry Kalinin; Alexander Golovyuk; George Krasnov; Vladislav Pavlov; Anna Kudryavtseva

doi:10.2298/AOO230608004S

Anastasiya Snezhkina EIMB RAS
Maria Fedorova Engelhardt Institute of Molecular Biology, Russian Academy of Sciences
Asiya Ayupova Engelhardt Institute of Molecular Biology, Russian Academy of Sciences
Elena Pudova Engelhardt Institute of Molecular Biology, Russian Academy of Sciences
Anastasiya Kobelyatskaya Engelhardt Institute of Molecular Biology, Russian Academy of Sciences
Dmitry Kalinin Vishnevsky Institute of Surgery, Ministry of Health of the Russian Federation
Alexander Golovyuk Vishnevsky Institute of Surgery, Ministry of Health of the Russian Federation
George Krasnov Engelhardt Institute of Molecular Biology, Russian Academy of Sciences
Vladislav Pavlov Engelhardt Institute of Molecular Biology, Russian Academy of Sciences
Anna Kudryavtseva Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

DOI: https://doi.org/10.2298/AOO230608004S

Keywords: Head and neck paraganglioma, vagal paraganglioma, SDHx mutations, high-throughput sequencing, transcriptome, PI3K-Akt signaling pathway

Abstract

Background: Vagal paraganglioma (VPGL) is a very rare neuroendocrine tumor arising from the paraganglion associated with the vagus nerve. VPGL is mainly characterized by an asymptomatic course and slow growth. However, up to 19% of tumors can metastasize. Due to the rarity of this tumor, information about VPGL is limited to single cases and small sample sets; the data on molecular genetic features is extremely scarce.

Methods: For the first time we have analyzed the enrichment of biological pathways associated with mutations in the SDHx genes in VPGLs. Bioinformatics analysis was performed based on the results of high-throughput transcriptome sequencing on an Illumina platform for 33 tumor tissues obtained from patients with vagal paragangliomas.

Results: Eight pathways of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database with gene overrepresentation (top-40 mode) have been identified. Significant changes were shown for the cancer-associated PI3K-Akt signaling pathway and interconnected pathways of focal adhesion and interaction of receptors with the extracellular matrix enriched by overexpressed genes.

Conclusion: Our result indicates the association of SDHx mutations with changes in the PI3K-Akt signaling pathway in vagal paraganglioma. The potential mechanism of deregulation in this pathway could be linked with a state of pseudohypoxia induced by the dysfunction of succinate dehydrogenase due to mutations in the SDHx genes.

Key words: Head and neck paraganglioma, vagal paraganglioma, SDHx mutations, high-throughput sequencing, transcriptome, PI3K-Akt signaling pathway.

References

1. El-Naggar A.K., Chan J.K.C., Grandis J.R., Takata T., Slootweg P.J. (2017) WHO Classification of Head and Neck Tumours. International Agency for Research on Cancer: Lyon, France.

2. Netterville J.L., Jackson C.G., Miller F.R., Wanamaker J.R., Glasscock M.E. (1998) Vagal paraganglioma: a review of 46 patients treated during a 20-year period. Arch Otolaryngol Head Neck Surg, 124(10):1133-1140.

3. Snezhkina A., Pavlov V., Dmitriev A., Melnikova N., Kudryavtseva A. (2021) Potential Biomarkers of Metastasizing Paragangliomas and Pheochromocytomas. Life (Basel), 11(11):1179

4. Boedeker C.C. (2011) Paragangliomas and paraganglioma syndromes. GMS Curr Top Otorhinolaryngol Head Neck Surg, 10:Doc03.

5. Snezhkina A.V., Fedorova M.S., Pavlov V.S., et al. (2020) Mutation Frequency in Main Susceptibility Genes Among Patients With Head and Neck Paragangliomas. Front Genet, 11:614908.

6. Kudryavtseva A.V., Kalinin D.V., Pavlov V.S., et al. (2020) Mutation profiling in eight cases of vagal paragangliomas. BMC Med Genomics, 13(Suppl 8):115.

7. Fishbein L., Leshchiner I., Walter V., et al. (2017) Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell, 31(2):181-193.

8. Zhikrivetskaya S.O., Snezhkina A.V., Zaretsky A.R., et al. (2017) Molecular markers of paragangliomas/pheochromocytomas. Oncotarget, 8(15):25756-25782.

9. Selak M.A., Armour S.M., MacKenzie E.D., et al. (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell, 7(1):77-85.

10. Letouze E., Martinelli C., Loriot C., et al. (2013) SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell, 23(6):739-752.

11. Fruman D.A., Rommel C. (2014) PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov, 13(2):140-156.

12. Adler J.T., Hottinger D.G., Kunnimalaiyaan M., Chen H. (2009) Inhibition of the PI3K pathway suppresses hormonal secretion and limits growth in pheochromocytoma cells. World J Surg, 33(11):2452-2457.

13. Robbins H.L., Hague A. (2015) The PI3K/Akt Pathway in Tumors of Endocrine Tissues. Front Endocrinol (Lausanne), 6:188.

14. Hayashi Y., Yokota A., Harada H., Huang G. (2019) Hypoxia/pseudohypoxia-mediated activation of hypoxia-inducible factor-1alpha in cancer. Cancer Sci, 110(5):1510-1517.

15. Zhong C., Tao B., Tang F., et al. (2021) Remodeling cancer stemness by collagen/fibronectin via the AKT and CDC42 signaling pathway crosstalk in glioma. Theranostics, 11(4):1991-2005.