Clinical exome next‑generation sequencing panel for hereditary pheochromocytoma and paraganglioma diagnosis

Melli,Beatrice; Cusenza,Vincenza Ylenia; Martinelli,Sandra; Castiglione,Federica; Fornaciari,Loretta; Palicelli,Andrea; Braglia,Luca; Farnetti,Enrico; Negro,Aurelio; Rosato,Simonetta; Frasoldati,Andrea; Baldini,Maicol; Grasselli,Chiara; Nicoli,Davide

doi:10.3892/etm.2024.12784

Clinical exome next‑generation sequencing panel for hereditary pheochromocytoma and paraganglioma diagnosis

Authors:
- Beatrice Melli
- Vincenza Ylenia Cusenza
- Sandra Martinelli
- Federica Castiglione
- Loretta Fornaciari
- Andrea Palicelli
- Luca Braglia
- Enrico Farnetti
- Aurelio Negro
- Simonetta Rosato
- Andrea Frasoldati
- Maicol Baldini
- Chiara Grasselli
- Davide Nicoli
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Affiliations: Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, I‑41125 Modena, Italy, Molecular Pathology, Azienda USL‑IRCCS di Reggio Emilia, I‑42123 Reggio Emilia, Italy, Pathology Unit, Azienda USL‑IRCCS di Reggio Emilia, I‑42123 Reggio Emilia, Italy, Statistic Unit, Clinical Trial Center, SOC Infrastructure, Research and Statistic, Azienda USL‑IRCCS di Reggio Emilia, I‑42123 Reggio Emilia, Italy, Cardiovascular Medicine Unit‑Hypertension Unit, Azienda USL‑IRCCS di Reggio Emilia, I‑42123 Reggio Emilia, Italy, Clinical Genetics Unit, Azienda USL‑IRCCS di Reggio Emilia, I‑42123 Reggio Emilia, Italy, Endocrinology Unit, Azienda USL‑IRCCS di Reggio Emilia, I‑42123 Reggio Emilia, Italy
Published online on: December 18, 2024 https://doi.org/10.3892/etm.2024.12784
Article Number: 34
Copyright: © Melli et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with an annual incidence of ~2 cases per million worldwide. The hereditary form is more likely to present in younger patients. To date, PPGL is considered a complex pathology that is difficult to diagnose. The present study aimed to improve the molecular diagnosis and other driver mutations related to PPGLs using TruSight One clinical exome panel (Illumina, Inc.). The clinical protocol used involved examining 28 patients with suspicion of genetic alterations as the cause of PPGLs. The variants of genes commonly associated with PPGLs (RET, FH, VHL, SDHA, SDHB, SDHC, SDHD, NF1, MAX, HIF2A, TMEM127 and TP53) were filtered across the panel. The libraries were sequenced on a MiSeq instrument (Illumina, Inc.) and the result was ≥20X coverage on 95% of the target regions in the panel, calculated by averaging the mean coverage for each exon. The results of sequencing detected 7% of pathogenic variants in the 18‑40 years age subgroup and 11% in the 41‑59 years age subgroup, whereas no pathogenic/likely pathogenic variants were identified in patients ≥60 years old. The identification of a germline mutation in patients with apparently sporadic PPGLs could lead to an early diagnosis of multiple or more aggressive tumors, or other neoplastic syndromes, in patients. Furthermore, this information may improve the development of targeted primary and secondary prevention programs tailored to these high‑risk groups.

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1	Lloyd RV, Osamura RY, Klöppel G and Rosai J: WHO classification of tumours of endocrine organs. Lloyd RV, Osamura RY, Klöppel G and Rosai J (eds). International Agency for Research on Cancer, 2017.
2	Pillai S, Gopalan V, Smith RA and Lam AKY: Updates on the genetics and the clinical impacts on phaeochromocytoma and paraganglioma in the new era. Crit Rev Oncol Hematol. 100:190–208. 2016.PubMed/NCBI View Article : Google Scholar
3	Gómez AM, Soares DC, Costa AAB, Pereira DP, Achatz MI and Formiga MN: Pheochromocytoma and paraganglioma: Implications of germline mutation investigation for treatment, screening, and surveillance. Arch Endocrinol Metab. 63:369–375. 2019.PubMed/NCBI View Article : Google Scholar
4	Seo SH, Kim JH, Kim MJ, Cho SI, Kim SJ, Kang H, Shin CS, Park SS, Lee KE and Seong MW: Whole exome sequencing identifies novel genetic alterations in patients with pheochromocytoma/paraganglioma. Endocrinol Metab (Seoul). 35:909–917. 2020.PubMed/NCBI View Article : Google Scholar
5	Farrugia FA and Charalampopoulos A: Pheochromocytoma. Endocr Regul. 53:191–212. 2019.PubMed/NCBI View Article : Google Scholar
6	Phillips RA, Manger WM and Gifford RW: Pheochromocytoma. J Clin Hypertens. 4:62–72. 2002.
7	Carrasquillo JA, Chen CC, Jha A, Ling A, Lin FI, Pryma DA and Pacak K: Imaging of pheochromocytoma and paraganglioma. J Nucl Med. 62:1033–1042. 2021.PubMed/NCBI View Article : Google Scholar
8	Nölting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, Eisenhofer G, Grossman A and Pacak K: Personalized management of pheochromocytoma and paraganglioma. Endocr Rev. 43:199–239. 2022.PubMed/NCBI View Article : Google Scholar
9	Huang Y, Wang LA, Xie Q, Pang J, Wang L, Yi Y, Zhang J, Zhang Y, Chen R, Lan W, et al: Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients. Endocr Connect. 7:1217–1225. 2018.PubMed/NCBI View Article : Google Scholar
10	Negro A, Nicoli D, Cavazza A, Santi R, Bonilauri S, Farnetti E and Panebianco M: A rare case of carney-stratakis syndrome in a patient with SDHA mutation. J Med Cases. 8:191–195. 2017.
11	Negro A, Graiani G, Nicoli D, Farnetti E, Casali B, Verzicco I, Tedeschi S, Ghirarduzzi A, Cannone V, Marco LDE, et al: Concurrent heterozygous Von-Hippel-Lindau and transmembrane-protein-127 gene mutation causing an erythropoietin-secreting pheochromocytoma in a normotensive patient with severe erythrocytosis. J Hypertens. 38:340–346. 2020.PubMed/NCBI View Article : Google Scholar
12	Adachi Y, Mita H, Sasaki Y, Himori R, Onodera K, Nakamura M, Kikuchi T, Yamashita K, Yoshida Y, Ishii Y and Endo T: Malignant paraganglioma of the posterior mediastinum: A case report with genetic analysis. Mol Clin Oncol. 10:10–16. 2019.PubMed/NCBI View Article : Google Scholar
13	Sarkadi B, Liko I, Nyiro G, Igaz P, Butz H and Patocs A: Analytical performance of NGS-based molecular genetic tests used in the diagnostic workflow of pheochromocytoma/paraganglioma. Cancers (Basel). 13(4219)2021.PubMed/NCBI View Article : Google Scholar
14	Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, Jang W, et al: ClinVar: Improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 46(D1062)2018.PubMed/NCBI View Article : Google Scholar
15	Rodrigues EDS, Griffith S, Martin R, Antonescu C, Posey JE, Coban-Akdemir Z, Jhangiani SN, Doheny KF, Lupski JR, Valle D, et al: Variant-level matching for diagnosis and discovery: Challenges and opportunities. Hum Mutat. 43(782)2022.PubMed/NCBI View Article : Google Scholar
16	Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, Boutselakis H, Cole CG, Creatore C, Dawson E, et al: COSMIC: The catalogue of somatic mutations in cancer. Nucleic Acids Res. 47:D941–D947. 2019.PubMed/NCBI View Article : Google Scholar
17	Khalaf S, Jamal HF, Alawi ZS and Alsaeed M: Bilateral pheochromocytoma and paraganglioma tumors due to von hippel-lindau syndrome in a 15-year-old boy: A case report. Cureus. 15(e47787)2023.PubMed/NCBI View Article : Google Scholar
18	Rednam SP, Erez A, Druker H, Janeway KA, Kamihara J, Kohlmann WK, Nathanson KL, States LJ, Tomlinson GE, Villani A, et al: Von hippel-lindau and hereditary pheochromocytoma/paraganglioma syndromes: Clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 23:e68–e75. 2017.PubMed/NCBI View Article : Google Scholar
19	Gniado E, Carracher CP and Sharma S: Simultaneous occurrence of germline mutations of SDHB and TP53 in a patient with metastatic pheochromocytoma. J Clin Endocrinol Metab. 105:991–995. 2020.PubMed/NCBI View Article : Google Scholar
20	Lima JV Jr, Scalissi NM, de Oliveira KC, Lindsey SC, Olivati C, Ferreira EN and Kater CE: Germline genetic variants in pheochromocytoma/paraganglioma: Single-center experience. Endocr Oncol. 3(e220091)2023.PubMed/NCBI View Article : Google Scholar
21	Nölting S, Ullrich M, Pietzsch J, Ziegler CG, Eisenhofer G, Grossman A and Pacak K: Current management of pheochromocytoma/paraganglioma: A guide for the practicing clinician in the era of precision medicine. Cancers (Basel). 11(1505)2019.PubMed/NCBI View Article : Google Scholar
22	Taïeb D, Hicks RJ, Hindié E, Guillet BA, Avram A, Ghedini P, Timmers HJ, Scott AT, Elojeimy S, Rubello D, et al: European association of nuclear medicine practice guideline/society of nuclear medicine and molecular imaging procedure standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 46:2112–2137. 2019.PubMed/NCBI View Article : Google Scholar
23	Su TW, Zhong X, Ye L, Song W, Jiang L, Xie J, Jiang Y, Zhou W, Zhang C, Wu L, et al: A nomogram for predicting the presence of germline mutations in pheochromocytomas and paragangliomas. Endocrine. 66:666–672. 2019.PubMed/NCBI View Article : Google Scholar
24	Sbardella E, Cranston T, Isidori AM, Shine B, Pal A, Jafar-Mohammadi B, Sadler G, Mihai R and Grossman AB: Routine genetic screening with a multi-gene panel in patients with pheochromocytomas. Endocrine. 59:175–182. 2018.PubMed/NCBI View Article : Google Scholar
25	Sarkadi B, Liko I, Nyiro G, Igaz P, Butz H and Patocs A: Analytical performance of ngs-based molecular genetic tests used in the diagnostic workflow of pheochromocytoma/paraganglioma. Cancers (Basel). 13:2021.PubMed/NCBI View Article : Google Scholar
26	Mellid S, Gil E, Letón R, Caleiras E, Honrado E, Richter S, Palacios N, Lahera M, Galofré JC, López-Fernández A, et al: Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma. Front Endocrinol (Lausanne). 13(1070074)2023.PubMed/NCBI View Article : Google Scholar