12488 Exome Sequencing Unravels New Susceptibility Genes For Pheochromocytomas And Paragangliomas

Abstract Disclosure: G. F. Fagundes: None. F. F. Castro: None. L. S. Santana: None. A. F. Afonso: None. A. W. Maciel: None. F. L. Ledesma: None. C. A. Pereira: None. I. C. Soares: None. D. M. Lourenço Junior: None. M. A. Pereira: None. V. Srougi: None. F. Y. Tanno: None. J. L. Chambo: None. M. C. Fragoso: None. A. O. Hoff: None. B. B. Mendonca: None. A. Latronico: None. M. Q. Almeida: None. Background: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with a high association with hereditary disease, affecting 40% of the cases. PPGL susceptibility genes are categorized into three clusters based on their pathophysiological and metabolomic mechanisms. Somatic oncogenic variants are identified in 30% of the tumors. Most of the germline and somatic drivers are mutually exclusive in PPGLs. Thus, 30% of the PPGLs remain without known genetic causes. Aim: To investigate new susceptibility genes for PPGLs using whole exome sequencing. Methods: We included 145 index patients with PPGLs (93 female and 52 male) with 91 pheochromocytomas (PHEO) and 60 paragangliomas, of which 43 (29. 65%) were metastatic. A target next-generation sequencing panel for susceptibility genes was initially performed. Whole exome sequencing was performed in 56 patients with PPGLs (38 were paired with tumor DNA). Results: SDHB was the most frequently affected gene in 29 of 145 patients (20%). Germline SDHB exon 1 deletion was identified in 14 patients (48. 27%). Germline variants were identified as follow: RET 22 (15. 17%), VHL 13 (8. 96%), SDHA 6 (4. 14%), SDHD 5 (3. 45%), NF1 5 (3. 45%), FH 2 (1. 38%), MAX 2 (1. 38%), DLST 1 (0. 69%), TMEM127 1 (0. 69%), SDHC 1 (0. 69%) and H3F3A 1 (0. 69%) case. Somatic variants were identified in 21 tumors: NF1 6 (4. 14%), HRAS 5 (3. 45%), VHL 2 (1. 38%), FGFR1 2 (1. 38%), and RET 1 (0. 69%). Six variants (five germline and one somatic) were identified in 3 new candidate genes: 1) Three very rare germline CHEK2 likely pathogenic or pathogenic variants (c. 475TC/ p. Tyr159His; c. 362GA/ p. Cys121Tyr; c. 319+2TA) in one metastatic PHEO and two PGLs (one metastatic). The metastatic PGL did not harbor any somatic oncogenic variant, while exome sequencing of a metastatic lesion from the PHEO had a somatic likely oncogenic HRAS variant; 2) Two very rare germline BRCA2 pathogenic variants (c. 3680₃681delTG/ p. Leu1227fs; c. 7806-2AC) in a 33-year-old man with non-metastatic PHEO and in a 25-year-old man with metastatic PGL. All germline variants have not been reported in the Brazilian genomic variant repository. Exome sequencing did not reveal any somatic oncogenic driver in both tumors; 3) The somatic GNAS likely oncogenic variant c. 601CT/ p. Arg201Cys in a pheochromocytoma. The prevalence of CHEK2 and BRCA2 pathogenic or likely pathogenic variants in our cohort were significantly higher compared with those in the gnomAD population database (p 0. 0001 and p = 0. 0004, respectively). Co-occurrence of germline and somatic drivers were found in 3 cases: FH and FGFR1, DLST and NF1, and CHEK2 and HRAS. In summary, germline and somatic diagnosis were reached in 63. 45% and 15. 18% of the PPGLs in our cohort, respectively. Conclusion: Our findings support CHEK2, BRCA2 and GNAS as novel susceptibility genes for PPGLs. Support: Sao Paulo Research Foundation (FAPESP) grant 2019/15873-6. Presentation: 6/2/2024