Abstract 2559: Genotype-phenotype associations in von hippel-lindau syndrome: Implications for screening
Authors: Murray Nicole , Leavitt Colton , Shepard Noah , Gonzales Zera , Li Jiaming , O'Neil Brock , Dechet Christopher , Schmidt Bogdana , Maughan Benjamin L. , Pauley Kristen , Naumer Anne , Kohlmann Wendy , Sanchez Alejandro 
Published: March 2024

Introduction and Objectives: Von Hippel-Lindau (VHL) is an autosomal dominant genetic disease. The type of VHL alteration has been shown to impact downstream VHL expression and clinical phenotype. However, current screening practices do not differ based on VHL genetic subtype. We aim to define the genotype-phenotype association among an institutional cohort of VHL patients.

Methods: We conducted a retrospective cohort study of 69 patients (27 families) with von Hippel-Lindau at the Huntsman Cancer Institute from 1998-2023. 55% (38/69) patients have documented VHL variants for review. We evaluated the association of VHL type with risk of pheochromocytoma (Pheo), renal cancer (RCC), and hemangioblastoma (HB). t test and Fisher’s exact test were used to assess differences in clinicopathologic characteristics by VHL Type. P-value &lt; 0.05 was considered significant.

Results: We identified 24 unique VHL alterations among 38 patients. 66% (25/38) of patients had missense mutations, 10% (4/38) nonsense mutations, 21% (8/38) splice mutations, and 3% (1/38) deletion/duplication (Table 1). The median age at VHL diagnosis was 31 years old (range 4-76). VHL Type 2 was more common, 87% (33/38). All VHL Type 1 patients (5/5) developed RCC and HB. No patients with VHL Type 1 developed PheoPara. Of the VHL Type 2 patients, 39% (13/33) have not developed any VHL-associated clinical manifestations. Of the 33 patients diagnosed with VHL Type 2, 18% (6/33) were diagnosed with PheoPara, 30% (10/33) with RCC, and 48% (16/33) with HB.

Conclusion: VHL type 2 comprised the majority of VHL diagnoses in our cohort with a notable absence of PheoPara phenotype. VHL Type 1 had higher penetrance and a higher prevalence for RCC and hemangioblastoma. With validation in larger cohorts, this cohort supports utilizing VHL genetic subtypes to personalize surveillance. Additional VHL testing for the remainder of the cohort is ongoing.

Clinicopathologic characteristics of von Hippel-Lindau Syndrome cohort with known genetic mutations All (n=38) Type 1 (n=5) Type 2 (n=33) p-value AgeMean (Median) 33.1 (31) 42 (28) 31.7 (31) 0.38 White, n (%) 92% (n=35) 5 (100%) 30 (91%) 1 Hispanic, n (%) 8% (n=3) - 3 (9%) 1 VHL alteration, n (%) - Missense 25 (66%) - 25 (76%) Nonsense 4 (10%) 4 (80%) - Splice site 8 (21%) - 8 (24%) Deletion/Duplication 1 (3%) 1 (20%) - Penetrance, n (%) 25 (66%) 5 (100%) 20 (61%) 0.14 Phenotype, n (%) PheoPara 6 (16%) - 6 (18%) 0.57 RCC 15 (39%) 5 (100%) 10 (30%) 0.006 Hemangioblastoma 21 (55%) 5 (100%) 16 (48%) 0.26

Citation Format: Nicole Murray, Colton Leavitt, Noah Shepard, Zera Gonzales, Jiaming Li, Brock O'Neil, Christopher Dechet, Bogdana Schmidt, Benjamin L. Maughan, Kristen Pauley, Anne Naumer, Wendy Kohlmann, Alejandro Sanchez. Genotype-phenotype associations in von hippel-lindau syndrome: Implications for screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2559.