Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma
Main Article Content
Keywords
paraganglioma, pheochromocytoma, targeted sequencing, susceptibility genes
Abstract
The aim of this study was to evaluate germline variant frequencies of pheochromocytoma and paraganglioma targeted susceptibility genes with next-generation sequencing method. Germline DNA from 75 cases were evaluated with targeted next-generation sequencing on an Illumina NextSeq550 instrument. KIF1B, RET, SDHB, SDHD, TMEM127, and VHL genes were included in the study, and Sanger sequencing was used for verifying the variants. The pathogenic/likely pathogenic variants were in the VHL, RET, SDHB, and SDHD genes, and the diagnosis rate was 24% in this study. Three different novel pathogenic variants were determined in five cases. This is the first study from Turkey, evaluating germline susceptibility genes of pheochromocytoma and paraganglioma with a detection rate of 24% and three novel variants. All patients with pheochromocytoma and paraganglioma need clinical genetic testing with expanded targeted gene panels for higher diagnosis rates.
References
1. Guilmette J, Sadow PM. A guide to pheochromocytomas and paragangliomas. Surg Pathol Clin. 2019 Dec;12(4):951–65. http://dx.doi.org/10.1016/j.path.2019.08.009
2. Kiernan CM, Solórzano CC. Pheochromocytoma and paraganglioma: Diagnosis, genetics, and treatment. Surg Oncol Clin N Am. 2016 Jan;25(1):119–38. http://dx.doi.org/10.1016/j. soc.2015.08.006
3. Farrugia FA, Martikos G, Tzanetis P, Charalampopoulos A, Misiakos E, Zavras N, et al. Pheochromocytoma, diagnosis and treatment: Review of the literature. Endocr Regul. 2017 Jul 1;51(3):168–81. http://dx.doi.org/10.1515/enr-2017-0018
4. Sanford T, Gomella PT, Siddiqui R, Su D, An JY, Bratslavsky G, et al. Long term outcomes for patients with von Hippel-Lindau and pheochromocytoma: Defining the role of active surveillance. Urol Oncol. 2021;39(2):134.e1–e8. http://dx.doi.org/10.1016/j. urolonc.2020.11.019
5. Fields FR, Suresh N, Hiller M, Freed SD, Haldar K, Lee SW. Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein. PLoS One. 2020 Nov 5;15(11):e0234100. http://dx.doi.org/10.1371/journal.pone.0234100
6. Kreusel KM. Ophthalmological manifestations in VHL and NF 1: Pathological and diagnostic implications. Fam Cancer. 2005;4:43–47. http://dx.doi.org/10.1007/s10689-004-1327-0
7. Dollfus H, Massin P, Taupin P, Nemeth C, Amara S, Giraud S, et al. Retinal hemangioblastoma in von Hippel-Lindau disease: A clinical and molecular study. Invest Ophthalmol Vis Sci. 2002;43:3067–74.
8. Ma X, Li M, Tong A, Wang F, Cui Y, Zhang X, et al. Genetic and clinical profiles of pheochromocytoma and paraganglioma: A single center study. Front Endocrinol (Lausanne). 2020 Dec 11;11:574662. http://dx.doi.org/10.3389/fendo.2020.574662
9. Irwin T, Konnick EQ, Tretiakova MS. Malignant intrarenal/ renal pelvis paraganglioma with co-occurring SDHB and ATRX mutations. Endocr Pathol. 2019 Dec;30(4):270–5. http:// dx.doi.org/10.1007/s12022-019-09594-1
10. Else T, Greenberg S, Fishbein L. Hereditary paraganglioma-pheochromocytoma syndromes. In: Adam MP, Ardinger HH, Pagon RA, et al. editors. GeneReviews®. Seattle, WA: University of Washington; 2008 [Updated 2018 Oct 4], p. 1993–2020.
11. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405–24. http://dx.doi.org/10.1038/gim.2015.30
12. den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016 Jun;37(6):564–9. http://dx.doi.org/10.1002/humu.22981
13. Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: Improving access to variant inter-pretations and supporting evidence. Nucleic Acids Res. 2018 Jan 4;46(D1):D1062–7. http://dx.doi.org/10.1093/nar/gkx1153
14. Welander J, Andreasson A, Juhlin CC, Wiseman RW, Bäckdahl M, Höög A, et al. Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2014 Jul;99(7):E1352–60. http://dx.doi.org/10.1210/jc.2013-4375
15. Kittah NE, Gruber LM, Bancos I, Hamidi O, Tamhane S, Iñiguez-Ariza N, et al. Bilateral pheochromocytoma: Clinical characteristics, treatment and longitudinal follow-up. Clin Endocrinol (Oxf). 2020 Sep;93(3):288–95. http://dx.doi. org/10.1111/cen.14222
16. Fagin JA, Wells SA, Jr. Biologic and clinical perspectives on thyroid cancer. N Engl J Med. 2016;15(375):1054–67. http://dx.doi. org/10.1056/NEJMra1501993
17. Siqueira DR, Ceolin L, Ferreira CV, Romitti M, Maia SC, Maciel LM, et al. Role of RET genetic variants in MEN2-associated pheochromocytoma. Eur J Endocrinol. 2014 Jun;170(6):821–8. http://dx.doi.org/10.1530/EJE-14-0084
18. Thosani S, Ayala-Ramirez M, Palmer L, Hu MI, Rich T, Gagel RF, et al. The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2013 Nov;98(11):E1813–19. http://dx.doi.org/10.1210/jc.2013-1653
19. Maciel RMB, Camacho CP, Assumpção LVM, Bufalo NE, Carvalho AL, de Carvalho GA, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: The BrasMEN study. Endocr Connect. 2019 Mar 1;8(3):289–98. http://dx.doi.org/10.1530/EC-18-0506
20. Febrero B, Rodríguez JM, Ríos A, Segura P, Pérez-Sánchez B, Torregrosa N, et al. Prophylactic thyroidectomy in multiple endocrine neoplasia 2 (MEN2) patients with the C634Y muta-tion: A long-term follow-up in a large single-center cohort. Eur J Surg Oncol. 2019 Apr;45(4):625–30. http://dx.doi.org/10.1016/j. ejso.2018.09.002
21. Ting KR, Ong PY, Wei SOG, Parameswaran R, Khoo CM, Deepak DS, et al. Characteristics and genetic testing outcomes of patients with clinically suspected paraganglioma/pheochromocytoma (PGL/PCC) syndrome in Singapore. Hered Cancer Clin Pract. 2020 Dec 11;18(1):24. http://dx.doi.org/10.1186/ s13053-020-00156-9
22. Korkmaz FN, Gokcay Canpolat A, Bilezikci B, Gurkan H, Erdogan MF. A patient with an atypic neck mass lesion. Acta Endocrinol (Buchar). 2020 Apr–Jun;16(2):232–5. http://dx.doi. org/10.4183/aeb.2020.232
23. Main AM, Rossing M, Borgwardt L, Grønkær Toft B, Rasmussen ÅK, Rasmussen UF. Genotype-phenotype associations in PPGLs in 59 patients with variants in SDHX genes. Endocr Connect. 2020 Aug;9(8):793–803. http://dx.doi. org/10.1530/EC-20-0279
24. Saie C, Buffet A, Abeillon J, Drui D, Leboulleux S, Bertherat J, et al. Screening of a large cohort of asymptomatic SDHx muta-tion carriers in routine practice. J Clin Endocrinol Metab. 2020 Nov 28:dgaa888. http://dx.doi.org/10.1210/clinem/dgaa888
25. Mannelli M, Castellano M, Schiavi F, Filetti S, Giacchè M, Mori L, et al. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009 May;94(5):1541–7. http://dx.doi.org/10.1210/jc.2008-2419
26. Turkova H, Prodanov T, Maly M, Martucci V, Adams K, Widimsky J Jr, et al. Character?st?cs and outcomes of meta-static SDHB and sporadic pheochromocytoma/paragangl?oma: An national institutes of health study. Endocr Pract. 2016 Mar;22(3):302–14. http://dx.doi.org/10.4158/EP15725.OR
27. Muth A, Crona J, Gimm O, Elmgren A, Filipsson K, Stenmark Askmalm M, et al. Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma. J Intern Med. 2019 Feb;285(2):187–204. http://dx.doi.org/10.1111/joim.12869
28. Algun E, Abaci N, Kosem M, Kotan C, Koseoglu B, Boztepe H, et al. Clinical characteristics and genetic screening of an extended family with MEN2A. J Endocrinol Invest. 2002 Jul– Aug;25(7):603–8. http://dx.doi.org/10.1007/BF03345083
29. Dagdeviren Cakir A, Turan H, Aykut A, Durmaz A, Ercan O, Evliyaoglu O. Two childhood pheochromocytoma cases due to von Hippel-Lindau disease, one associated with pancreatic neuroendocrine tumor: A very rare manifestation. J Clin Res Pediatr Endocrinol. 2018 Jun 1;10(2):179–82. http://dx.doi. org/10.4274/jcrpe.5078
2. Kiernan CM, Solórzano CC. Pheochromocytoma and paraganglioma: Diagnosis, genetics, and treatment. Surg Oncol Clin N Am. 2016 Jan;25(1):119–38. http://dx.doi.org/10.1016/j. soc.2015.08.006
3. Farrugia FA, Martikos G, Tzanetis P, Charalampopoulos A, Misiakos E, Zavras N, et al. Pheochromocytoma, diagnosis and treatment: Review of the literature. Endocr Regul. 2017 Jul 1;51(3):168–81. http://dx.doi.org/10.1515/enr-2017-0018
4. Sanford T, Gomella PT, Siddiqui R, Su D, An JY, Bratslavsky G, et al. Long term outcomes for patients with von Hippel-Lindau and pheochromocytoma: Defining the role of active surveillance. Urol Oncol. 2021;39(2):134.e1–e8. http://dx.doi.org/10.1016/j. urolonc.2020.11.019
5. Fields FR, Suresh N, Hiller M, Freed SD, Haldar K, Lee SW. Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein. PLoS One. 2020 Nov 5;15(11):e0234100. http://dx.doi.org/10.1371/journal.pone.0234100
6. Kreusel KM. Ophthalmological manifestations in VHL and NF 1: Pathological and diagnostic implications. Fam Cancer. 2005;4:43–47. http://dx.doi.org/10.1007/s10689-004-1327-0
7. Dollfus H, Massin P, Taupin P, Nemeth C, Amara S, Giraud S, et al. Retinal hemangioblastoma in von Hippel-Lindau disease: A clinical and molecular study. Invest Ophthalmol Vis Sci. 2002;43:3067–74.
8. Ma X, Li M, Tong A, Wang F, Cui Y, Zhang X, et al. Genetic and clinical profiles of pheochromocytoma and paraganglioma: A single center study. Front Endocrinol (Lausanne). 2020 Dec 11;11:574662. http://dx.doi.org/10.3389/fendo.2020.574662
9. Irwin T, Konnick EQ, Tretiakova MS. Malignant intrarenal/ renal pelvis paraganglioma with co-occurring SDHB and ATRX mutations. Endocr Pathol. 2019 Dec;30(4):270–5. http:// dx.doi.org/10.1007/s12022-019-09594-1
10. Else T, Greenberg S, Fishbein L. Hereditary paraganglioma-pheochromocytoma syndromes. In: Adam MP, Ardinger HH, Pagon RA, et al. editors. GeneReviews®. Seattle, WA: University of Washington; 2008 [Updated 2018 Oct 4], p. 1993–2020.
11. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405–24. http://dx.doi.org/10.1038/gim.2015.30
12. den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016 Jun;37(6):564–9. http://dx.doi.org/10.1002/humu.22981
13. Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: Improving access to variant inter-pretations and supporting evidence. Nucleic Acids Res. 2018 Jan 4;46(D1):D1062–7. http://dx.doi.org/10.1093/nar/gkx1153
14. Welander J, Andreasson A, Juhlin CC, Wiseman RW, Bäckdahl M, Höög A, et al. Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2014 Jul;99(7):E1352–60. http://dx.doi.org/10.1210/jc.2013-4375
15. Kittah NE, Gruber LM, Bancos I, Hamidi O, Tamhane S, Iñiguez-Ariza N, et al. Bilateral pheochromocytoma: Clinical characteristics, treatment and longitudinal follow-up. Clin Endocrinol (Oxf). 2020 Sep;93(3):288–95. http://dx.doi. org/10.1111/cen.14222
16. Fagin JA, Wells SA, Jr. Biologic and clinical perspectives on thyroid cancer. N Engl J Med. 2016;15(375):1054–67. http://dx.doi. org/10.1056/NEJMra1501993
17. Siqueira DR, Ceolin L, Ferreira CV, Romitti M, Maia SC, Maciel LM, et al. Role of RET genetic variants in MEN2-associated pheochromocytoma. Eur J Endocrinol. 2014 Jun;170(6):821–8. http://dx.doi.org/10.1530/EJE-14-0084
18. Thosani S, Ayala-Ramirez M, Palmer L, Hu MI, Rich T, Gagel RF, et al. The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 2013 Nov;98(11):E1813–19. http://dx.doi.org/10.1210/jc.2013-1653
19. Maciel RMB, Camacho CP, Assumpção LVM, Bufalo NE, Carvalho AL, de Carvalho GA, et al. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: The BrasMEN study. Endocr Connect. 2019 Mar 1;8(3):289–98. http://dx.doi.org/10.1530/EC-18-0506
20. Febrero B, Rodríguez JM, Ríos A, Segura P, Pérez-Sánchez B, Torregrosa N, et al. Prophylactic thyroidectomy in multiple endocrine neoplasia 2 (MEN2) patients with the C634Y muta-tion: A long-term follow-up in a large single-center cohort. Eur J Surg Oncol. 2019 Apr;45(4):625–30. http://dx.doi.org/10.1016/j. ejso.2018.09.002
21. Ting KR, Ong PY, Wei SOG, Parameswaran R, Khoo CM, Deepak DS, et al. Characteristics and genetic testing outcomes of patients with clinically suspected paraganglioma/pheochromocytoma (PGL/PCC) syndrome in Singapore. Hered Cancer Clin Pract. 2020 Dec 11;18(1):24. http://dx.doi.org/10.1186/ s13053-020-00156-9
22. Korkmaz FN, Gokcay Canpolat A, Bilezikci B, Gurkan H, Erdogan MF. A patient with an atypic neck mass lesion. Acta Endocrinol (Buchar). 2020 Apr–Jun;16(2):232–5. http://dx.doi. org/10.4183/aeb.2020.232
23. Main AM, Rossing M, Borgwardt L, Grønkær Toft B, Rasmussen ÅK, Rasmussen UF. Genotype-phenotype associations in PPGLs in 59 patients with variants in SDHX genes. Endocr Connect. 2020 Aug;9(8):793–803. http://dx.doi. org/10.1530/EC-20-0279
24. Saie C, Buffet A, Abeillon J, Drui D, Leboulleux S, Bertherat J, et al. Screening of a large cohort of asymptomatic SDHx muta-tion carriers in routine practice. J Clin Endocrinol Metab. 2020 Nov 28:dgaa888. http://dx.doi.org/10.1210/clinem/dgaa888
25. Mannelli M, Castellano M, Schiavi F, Filetti S, Giacchè M, Mori L, et al. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009 May;94(5):1541–7. http://dx.doi.org/10.1210/jc.2008-2419
26. Turkova H, Prodanov T, Maly M, Martucci V, Adams K, Widimsky J Jr, et al. Character?st?cs and outcomes of meta-static SDHB and sporadic pheochromocytoma/paragangl?oma: An national institutes of health study. Endocr Pract. 2016 Mar;22(3):302–14. http://dx.doi.org/10.4158/EP15725.OR
27. Muth A, Crona J, Gimm O, Elmgren A, Filipsson K, Stenmark Askmalm M, et al. Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma. J Intern Med. 2019 Feb;285(2):187–204. http://dx.doi.org/10.1111/joim.12869
28. Algun E, Abaci N, Kosem M, Kotan C, Koseoglu B, Boztepe H, et al. Clinical characteristics and genetic screening of an extended family with MEN2A. J Endocrinol Invest. 2002 Jul– Aug;25(7):603–8. http://dx.doi.org/10.1007/BF03345083
29. Dagdeviren Cakir A, Turan H, Aykut A, Durmaz A, Ercan O, Evliyaoglu O. Two childhood pheochromocytoma cases due to von Hippel-Lindau disease, one associated with pancreatic neuroendocrine tumor: A very rare manifestation. J Clin Res Pediatr Endocrinol. 2018 Jun 1;10(2):179–82. http://dx.doi. org/10.4274/jcrpe.5078
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Mar 13, 2021
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Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma. (2021). Journal of Kidney Cancer, 8(1), 19-24. https://doi.org/10.15586/jkcvhl.v8i1.171
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Pheochromocytoma
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How to Cite
Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma. (2021). Journal of Kidney Cancer, 8(1), 19-24. https://doi.org/10.15586/jkcvhl.v8i1.171