Revisiting the VHL Connection: How a Common
Pathway Now More Closely Links Sporadic RCC,
VHL-Associated Syndromes
Eric Jonasch, MD
Professor, Department of
Genitourinary Medical Oncology
Division of Cancer Medicine
The University of Texas
MD Anderson Cancer Center
Houston, Texas
T
he trajectory of recent work on the pathophysiology of
renal cell carcinoma (RCC) suggests the extent to which
a spectrum of disorders share a common genetic framework.
Although the implications of losing the von Hippel-Lindau
(VHL) gene have been clear for a long time, an improved
understanding of its precise role in tumorigenesis is now emerging.
The challenge now is to take these new findings and extrapolate
them to treatment choices as we seek to optimize
clinical outcomes, not only in RCC but in VHL-related diseases.
A growing awareness of the interaction between germline
mutations and somatic tumor mutations has focused
more attention on how distinct phenotypes could provide
important new information with implications for
earlier diagnosis and potential management strategies in
hereditary and sporadic renal cell carcinoma (RCC). Advances
in genome-wide sequencing technologies have
helped move the discourse beyond core driver mutations,
including the VHL gene, to include additional mutations
that affect diverse elements of cellular biology, including
chromatin homeostasis. Armed with new data emerging
over the last few years, clinicians may have more effective
strategies to meet diagnostic, surveillance, and therapeutic
challenges in sporadic RCC and in hereditary VHL disease.
Although VHL disease is rare—occurring in roughly 1
in 36,000 births1- this syndrome could yield new clues regarding
the molecular pathogenesis of sporadic RCC and
could serve as a framework for the application of targeted
10 Kidney Cancer Journal
therapies. As more of the biology of VHL disease has unraveled,
the implications for potential therapeutic approaches,
including the use of antiangiogenic agents and
immunotherapy, suggest that we may have more effective
ways to have an impact on downstream targets in
RCC.
One of the major themes to emerge from newly published
work on VHL disease is the extent to which hereditary
and sporadic RCC share common features regarding
their molecular pathogenesis. These include dysregulation
of the VHL tumor suppressor protein/hypoxia inducible
factor axis, ciliogenesis and aberrant tumor metabolism.
2 As the knowledge base for all genetic RCC syndromes
expands, the focus is also shifting toward the de-
Keywords: von Hippel Lindau (VHL) disease; syndrome; hereditary,
genetic mutation; hemangioblastoma; retinal; hypoxia inducible
factor; VEGF.
Corresponding Author: Eric Jonasch, MD, Department of Genitourinary
Medical Oncology, Division of Cancer Medicine, The University
of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd # 853,
Houston, TX 77030; email address: EJonasch@mdanderson.org
Figure 1. (A) Axial T1 postcontrast images demonstrate an
enhancing mural nodule (white arrow) with accompanying cyst (*)
in the right cerebellar hemisphere exerting a mass effect upon the
midline and fourth ventricle (double white arrow). (B) Hematoxylineosin
staining showing scattered large hyperchromatic nuclei,
vacuolated cells, and multiple capillaries which are classic features
of the cellular type of hemangioblastoma. From: Varshney N,
Kebede AA, Owusu-Dapaah H, et al. A review of von-Hippel-Lindau
syndrome. J Kidney Cancer VHL. 2017;4:20-29.
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