Insights into the genetic landscape of pheochromocytomas and paragangliomas in a Brazilian cohort

Author(s):Show less -

Fagundes, Gustavo F. C. ; Freitas-Castro, Felipe ; Santana, Lucas S. ; Ledesma, Felipe L. ; Petenuci, Janaina ; Afonso, Ana Caroline F. ; Pereira, Caio A. A. ; Maciel, Ana Alice W. ; Soares, Ibere C. ; Gomes, Nathalia L. ; Lourenco, Delmar M. ; Pereira, Maria Adelaide A. ; Srougi, Victor ; Tanno, Fabio Y. ; Chambo, Jose L. ; Fragoso, Maria Candida B., V ; Hoff, Ana O. ; Mendonca, Berenice B. ; Latronico, Ana Claudia ; Almeida, Madson Q.

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF ENDOCRINOLOGY; v. 192, n. 1, p. 14-pg., 2025-01-06.

Abstract

Objective Germline and somatic drivers are identified in 30% and 40% of pheochromocytomas and paragangliomas (PPGLs), respectively. In this study, we investigated the genetic landscape of PPGLs in a Brazilian cohort. Methods We studied 182 index patients with PPGLs (116 females and 66 males), comprising 118 pheochromocytoma and 70 paraganglioma cases. Our optimized sequencing strategy included SANGER sequencing, targeted next-generation sequencing panel, and whole-exome sequencing. Results Germline and somatic pathogenic or likely pathogenic variants in susceptibility genes were identified in 88 (48.4%) and 18 (10.4%) cases, respectively. SDHB was the most frequently affected gene, identified in 30 patients (16.5%), with a germline SDHB exon 1 deletion present in 46.7% of these cases. The Brazilian cohort exhibited a higher rate of germline diagnoses when compared to the European (31%), American (27%), and Chinese (21%) cohorts (P < .001). Five germline variants in new susceptibility genes were identified: (1) Three CHEK2 likely pathogenic or pathogenic variants (c.475T > C/p.Tyr159His; c.362G > A/p.Cys121Tyr; c.319 + 2T > A); and (2) Two BRCA2 pathogenic variants (c.3680_3681delTG/p.Leu1227fs and c.7806-2A > C). These variants are unreported in the Brazilian genomic variant repository. CHEK2 immunostaining was negative in the three tumors, with one case exhibiting CHEK2 loss of heterozygosity. Moreover, the prevalence of CHEK2 or BRCA2 pathogenic or likely pathogenic variants in our cohort was significantly higher compared to global population databases (P < .0001 and P = .0004, respectively). Conclusion Our cohort of PPGLs demonstrated a high frequency of germline diagnoses. Additionally, our findings suggest CHEK2 and BRCA2 as potential susceptibility genes for PPGLs. (AU)

• FAPESP's process: 19/15873-6 - Investigation of new genetic, clinical and pathological aspects of endocrine arterial hypertension
• Grantee: Madson Queiroz Almeida
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/10363-0 - Whole exome sequencing for investigation of novel genetic causes of primary Aldosteronism caused by bilateral adrenal hyperplasia
• Grantee: Lucas Santos de Santana
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/11240-9 - Whole exome sequencing for the investigation of novel genetic causes of metastatic Pheochromocytomas and Paragangliomas
• Grantee: Felipe Freitas de Castro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/09879-1 - Clinical and genetic investigation of the association between Primary Aldosteronism and Papillary Thyroid Cancer
• Grantee: Ana Alice Wolf Maciel
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)