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Von Hippel Lindau Genetics - News-Medical.net
Von Hippel-Lindau (VHL) Syndrome is an inherited disorder that is caused by a mutation in the VHL gene, which leads to an increased risk of the development of tumors in the central nervous system (CNS) and viscera. This occurs due to changes in the production of proteins in the body, which are involved in the regulation of cell growth and division.
Von Hippel-Lindau (VHL) Syndrome is an inherited disorder that is caused by a genetic mutation. Image Credit: Billion Photos / Shutterstock
Von Hippel-Lindau GeneThe VHL gene is a tumor suppressor gene located on chromosome 3 at 3p25-26 that is responsible for monitoring cell growth and division and preventing the cells from multiplying uncontrollably.
There are several functions of the VHL gene within the body, one of which is to regulate the production of proteins in the VCB-CUL2 complex. This group of proteins ubiquitinates substrates in the body and marks them for degradation when they're not needed.
One of the key target proteins is hypoxia-inducible factor 2-alpha (HIF-2α), which plays a significant role in another protein complex referred to as HIF that affects the ability of an individual to adapt to atmospheric oxygen changes. This complex regulates the erythropoietin, which acts to control the production of red blood cells.
The VHL gene is likely to be involved with several other cellular functions, particularly those that control the growth and multiplication of cells. The exact mechanism of tumorigenesis is unknown, although there are several theories to describes the relationship. The healthy gene itself may suppress the growth of tumors, resulting in uncontrolled cell growth when there is a mutation.
Genetic InheritanceVHL gene mutations follow an autosomal dominant inheritance pattern. This means that one copy of the mutation, which may be inherited from either parent, is able to increase the risk of developing the tumors and VHL syndrome.
The majority of patients with the syndrome inherit the gene mutation from an affected parent, but approximately 1 in 5 patients have a spontaneous gene mutation with no family history of the disorder. This is likely to result from a mutation in the formation of the reproductive cells or the early development of the fetus.
VHL syndrome is distinct from most other autosomal dominant conditions because there should be two gene mutations present in order for tumors to begin forming, leading to the presentation of the syndrome. The second copy is altered during the person's lifetime in the cells of the brain, retina or kidneys but eventually affects nearly all individuals that inherit one gene mutation.
VHL Gene MutationWhen there are two mutations in the VHL gene, abnormal proteins are produced and the function of the gene is altered. In particular, the proteins in the VCB-CUL2 complex change and affect the regulation of cell growth in the body.
As a result of this, certain cells are able to divide more rapidly than usual and form tumors or cysts characteristic of VHL syndrome. These often include hemangioblastomas, renal cell carcinoma (RCC) renal cysts and phaeochromocytoma, as well as tumors in the pancreas, epididymis uterus or endolymphatic sac in the inner ear.
References Further ReadingLast Updated: Mar 11, 2021
VHL-Associated RCC Characterized By High Surgery, Low Response Rates
Patients with von Hippel-Lindau (VHL) disease who develop VHL-associated renal cell carcinoma (RCC) and do not receive systemic therapy have a high rate of disease progression and metastasis, a natural history study finds.
The hereditary cancer syndrome VHL is caused by pathogenic variants in the VHL tumor suppressor gene. Approximately 90% of patients with VHL are diagnosed with a related cancer by 65 years of age, with 70% developing RCC.
William Marston Linehan, MD, from the National Cancer Institute (NCI) in Bethesda, Maryland, and colleagues evaluated 2004-2020 NCI data on 244 patients with germline VHL pathogenic variants and at least 1 renal solid tumor sized 10 mm or larger for renal, oncologic, and survival outcomes. At diagnosis, the patients were aged a median 41 years and 45% were women. The largest renal tumor was 25 mm, and the total renal tumor burden was 45 mm, respectively.
Among the subset of 178 patients not receiving systemic therapies who underwent at least 3 radiographic assessments, 78% had stable disease, and 20% had progressive disease. The objective response rate (ORR) was 1.8% (95% CI, 0.37%-5.13%), Dr Linehan's team reported in European Urology.
The probability of experiencing no disease progression diminished over time: 69% at 2 years, 37% at 5 years, and 32% at 7 years.
Among 186 patients who underwent renal surgery, 96% underwent nephrectomy, (12% radical surgery; 93% partial nephrectomy). The largest renal tumor size before surgery was 34.6 mm on average.
The probability of not undergoing a first or second renal surgery was 70% and 78% at 2 years, 39% and 53% at 5 years, and 27% and 36% at 7 years, respectively.
The patients with either a faster linear growth rate of their renal tumors or larger renal tumor size/burden had significantly shorter times to the first and second surgery.
Preexisting chronic kidney disease (CKD) affected 24% of patients undergoing their first renal surgery. Of these, 80% had evidence of moderate to advanced CKD after surgery, including 25% with stage 3b, 22% with stage 4, and 19% with stage 5 CKD. Among patients without CKD before the first renal surgery, 28% had onset of moderate to advanced CKD, specifically stages 3b (35%), 4 (10%), and 2 (5.0%) CKD.
Metastases occurred in 12 patients and locally advanced disease in 1. The most common metastatic sites were the lungs (n=6) and the spine (n=3).
A total of 42 patients died during the study period, among whom the primary cause of death was VHL-related tumors for 18. CKD was a contributor to death in 5 patients.
"The results demonstrate that in the absence of systemic therapy, most patients experience disease progression with tumor growth, and undergo surgery associated with downstream morbidity and mortality. These results can be used to contextualize the antitumor effects of new systemic therapies including belzutifan," according to Dr Linehan's team.
Disclosure: This research was supported by Merck & Co Inc. Please see the original reference for a full list of disclosures
This article originally appeared on Renal and Urology News
DNA-Based Presymptomatic Diagnosis For The Von Hippel-Lindau ... - Nature
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