12488 Exome Sequencing Unravels New Susceptibility Genes For Pheochromocytomas And Paragangliomas
Authors: Fagundes G F , Castro F F , Santana L S , Afonso A F , Maciel A W , Ledesma F L , Pereira C A , Soares I C , Lourenço D M , Pereira M A , Srougi V , Tanno F Y , Chambo J L , Fragoso M C , Hoff A O , Mendonca B B , Latronico A , Almeida M Q 
Published: October 2024

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.475T&gt;C/ p.Tyr159His; c.362G&gt;A/ p.Cys121Tyr; c.319+2T&gt;A) 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.3680_3681delTG/ p.Leu1227fs; c.7806-2A&gt;C) 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.601C&gt;T/ 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 &lt; 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