Pathogenicity of germline VHL variants is associated with renal cell carcinoma size in von Hippel-Lindau disease

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Mori, Gustavo H. ; Fagundes, Gustavo F. C. ; Santana, Lucas S. ; Freitas-Castro, Felipe ; Afonso, Ana Caroline F. ; Lourenco, Delmar M. ; Pereira, Maria Adelaide A. ; Tanno, Fabio Y. ; Srougi, Victor ; Chambo, Jose L. ; Cordeiro, Mauricio D. ; Nahas, William C. ; Hoff, Ana O. ; Fragoso, Maria Candida B. V. ; Mendonca, Berenice B. ; Latronico, Ana Claudia ; Almeida, Madson Q.

• Document type: Journal article
• Source: ARCHIVES OF ENDOCRINOLOGY METABOLISM; v. 69, p. 6-pg., 2025-01-01.

Abstract

Objective: In this study, our aim was to search for new genotype-phenotype correlations in patients with Von Hippel-Lindau (VHL) disease. Subjects and methods: We retrospectively studied 53 consecutive patients with VHL disease and confirmed genetic diagnoses from 32 relatives. Results: Most VHL pathogenic or likely pathogenic variants were missense (18 out of 32; 56.25%). The median size of the large carcinoma (RCC) was 3.6 cm (interquartile range, 2.8 to 6.5 cm). Interestingly, the size of the large RCC in patients harboring VHL pathogenicvariants (n = 9) was significantly greater than that in patients with VHL likely pathogenic (n = 7) variants (5.4 cm [3.65 to 6.6] vs. 2.9 cm [2.45 to 3.35]; p = 0.008). Moreover, adrenal paraganglioma (PGL) (82.35% vs. 17.65%; p = 0.0001) and pancreatic neuroendocrine tumor (PNET) (81.81% vs. 18.18%; p = 0.007) were associated with missense VHL pathogenic or likely pathogenic variants compared with non-missense defects. In contrast, central nervous system (CNS) hemangioblastomas (HBs) (90.47% vs. 53.12%; p = 0.004), pancreatic cysts (76.19% vs. 28.12%; p = 0.001) and RCCs (57.14% vs. 12.5; p = 0.001) were more common in patients with non-missense VHL variants. Conclusion: VHL pathogenic variants were associated with larger RCCs than were VHL likely pathogenic variants. (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