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

TL;DR

This study found that certain genetic variants in VHL disease are linked to larger kidney tumors and different types of tumors in patients.

Contribution

The study identifies a novel correlation between VHL variant type and tumor characteristics, particularly larger renal cell carcinomas.

Findings

Patients with VHL pathogenic variants had significantly larger renal cell carcinomas compared to those with likely pathogenic variants.

Missense VHL variants were associated with adrenal paragangliomas and pancreatic neuroendocrine tumors.

Non-missense VHL variants were linked to higher occurrences of CNS hemangioblastomas, pancreatic cysts, and RCCs.

Abstract

In this study, our aim was to search for new genotype-phenotype correlations
in patients with Von Hippel-Lindau (VHL) disease.

We retrospectively studied 53 consecutive patients with VHL disease and
confirmed genetic diagnoses from 32 relatives.

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 pathogenic
variants (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.

VHL pathogenic variants were associated with larger RCCs than were
VHL likely pathogenic variants.

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