An overview from Professor Drake:
“Our research endeavours focus on the intricate understanding and treatment of von Hippel-Lindau (VHL) disease. We’re diligently amassing patient-specific specimens, notably tissue fragments that retain the tumour microenvironment’s vital characteristics. These fragments are pivotal in replicating the disease’s complexity. Our objective is to delve into the molecular mechanisms involved when VHL patients undergo Belzutifan therapy. By scrutinizing how Belzutifan functions across diverse tissues affected by VHL, we aspire to personalize treatment approaches and potentially influence therapeutic strategies for related conditions like renal cell carcinoma. We’re deeply appreciative of the generous support from VHL UK/Ireland, and this research holds immense promise for revolutionizing VHL disease treatment at a molecular level.”

December 1st, 2022 – The initial pilot phase of the registry has been completed and now wider participation is invited from all over the UK.

Anyone wishing to participate can contact  Study Coordinator Katerina Stroud on phone: 01223 746716 or email: Katerina.stroud2@nhs.net or the Chief Investigator Professor Eamonn Maher eamonn.maher@nhs.net or add-tr.humgendis@nhs.net

March 1st, 2024 – A meeting of the “Inherited Renal Cancer Syndromes” Rare Disease Group of the RaDaR Registry was held recently and attended by RDG group members including Prof Eamonn Maher (RDG Lead), Mr Rupesh Bhatt, Dr Lucas Foggensteiner, Mr Graham Lovitt (VHL/UK Ireland), Prof Marc Tischkowitz and Dr Emma Woodward. The group heard that recruitment to the registry had started in Cambridge and has now progressed to other centres. To date, 311 participants have been recruited with a variety of conditions including von Hippel-Lindau disease, PTEN hamartoma syndrome, Birt-Hogg-Dube syndrome, HLRCC and others. Plans to complete recruitment at currently participating centres and to add new centres were discussed.

June 7th 2024 – Some of this Charity’s Grant Award funding went towards Huairen Zhang’s PhD studentship and the following article has now been published.

Characteristics, aetiology and implications for management of multiple primary renal tumours: a systematic review

https://ukkidney.org/rare-renal/about

The 100K genomes project is a world-leading genomics study performed in the UK that has provided more than 100,000 whole genome sequences on individuals with a variety of rare diseases and cancers (including more than 1,000 kidney tumours). We are analysing the genetic alterations in VHL and other kidney genes in order to better classify the genetic variations in these genes. The results from these studies will make an important contribution to international efforts to improve genetic diagnosis of VHL disease and related disorders. *The initial grant award was for £40,000 and an additional grant award of £20,000 was made March 2021 to continue the work.

The VHL Alliance published in its Summer 2022 Newsletter an overview:

 ALTERATIONS IN THE ELOC GENE MAY CAUSE VHL DISEASE By Dr. Amit Tirosh, Sheba Medical Center.

“The diagnosis of von Hippel-Lindau disease (VHL) can be based on genetic testing or a combination of the typical manifestations. About 5% of VHL patients have a clinical VHL diagnosis, while lacking a positive result on a genetic test.
The VHL protein, the actual biological machinery encoded by the VHL gene, works in a complex with two other proteins called Elongin B and Elongin C, the latter encoded by the ELOC gene. A recent study by Andreou and others, led by the renowned Prof. Eamonn Maher from the UK, that was published in the journal Human Molecular Genetics, reported on a patient with VHL disease, with no variant identified in the VHL gene, but rather a variant in the ELOC gene. This finding makes “biological” sense and is further supported by scientific evidence from non-hereditary kidney cancer. The importance of this finding is in the possibility of diagnosing VHL based on variants in genes other than the VHL gene. Further research is needed to learn more”

The Human Molecular Genetics article published is:

Elongin C (ELOC/TCEB1)-associated von Hippel–Lindau disease cite 1.

It contains a detailed description of one patient with the specific ELOC Gene variant NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys). The patient has a clinical diagnosis of VHL with no VHL Gene variant.  The article describes the detailed analysis of the 100,000 Genome Project data and the finding that this variant was also absent from the germline of 78,195 participants including 1,336 individuals with RCC. Of these 1,336 individuals identified 8 had a candidate pathogenic ELOC somatic variant.

At the end of the article discussion:
“Currently, we would suggest that testing of ELOC should be performed in patients with suspected VHL disease but without an identifiable VHL mutation. The clinical course of ELOC-mutated RCC is variable (21); however, based on existing data, we would propose that individuals with a pathogenic germline variant should be managed as per VHL disease (40). While the emphasis of VHL management is primarily early diagnosis and treatment, the mechanistic similarities between VHL- and ELOC p.Tyr79Cys-associated tumours suggest that treatment with HIF-2α antagonists, such as bezultifan, may be a therapeutic option for ELOC-mutated tumours.”

The data of the 1,336 individuals with RCC was analysed in this further article

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases cite 2.

From the abstract:

“Whole-genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100 000 Genomes Project, a nationwide multicentre study, was analyzed to identify rare P/LP short variants (single nucleotide variants and insertions/deletions ranging from 1 to 50 base pairs) and structural variants in 121 CSGs.”

1. _{Human Molecular Genetics, Volume 31, Issue 16, 15 August 2022, Pages 2728–2737, https://doi.org/10.1093/hmg/ddac066}

2. _{Human Molecular Genetics, Volume 31, Issue 17, 1 September 2022, Pages 3001–3011, https://doi.org/10.1093/hmg/ddac089}

Some snippets taken from the project description.
Saturation genome editing (SGE)is a method that allows us to assay thousands of genetic variants in their endogenous genomic context. SGE was used previously to assay 3,893 SNVs in BRCA1 for functional effects at the mRNA and protein level in human HAP1 cells2. “Function scores” derived for each variant were highly accurate at distinguishing established pathogenic variants, indicating SGE data can aid clinical variant interpretation. Watch this YouTube video about SGE used for BRCA1.
Using SGE on VHL variants to produce a systematic genotype-phenotype map of VHL would prove useful for adjudicating which variants are pathogenic. Furthermore, by using multiple assays to study all possible coding variants, we will gain insights into how disruption of the gene’s distinct molecular functions correlates with clinical presentation.

This Grant Award was made possible from the fundraising by Charles White in 2020

This project was successfully completed in July 2024 with the publication of results in Nature Saturation genome editing maps the functional spectrum of pathogenic VHL alleles. This was announced in a press release from the Crick Institute.

This was the thank you the charity received from Carl Spickett, post-doctoral researcher working with Eamonn:

“First and foremost a big thank-you to everyone for all your fundraising efforts and generous donations for Eamonn’s research. We had some discussion on how to make best use of your donation and decided to use the funds to purchase an automated ‘Luna FL’ cell counter for our work. The donation also covered the consumables for use with the equipment for at least one year.

I’ve included some pictures and thought I’d write a bit to describe how it is being used. As you can see it has really brightened up the cell culture room where our equipment is predominantly plain! The screen is extremely helpful for both demonstration and as a tangible way for us to discuss the findings as we get them in real time.

Our laboratory grown cells are counted on a daily basis to make sure we use the same number of cells for each of our experiments. We’ve found the new counter to be very fast and extremely accurate for doing this compared to counting by hand! In addition we are able to simultaneously check the health of our cell lines and measure their size accurately which is important for some of our experiments.

More specifically we extensively use kidney tumour cell lines to study disease progression. Since the cell counter is accurate over a range of cell types and shapes it is proving extremely accurate for use with these particular cells.

I hope this illustrates how this counter is not only extremely helpful for the specific applications of our work but also for the day-to-day tasks we need to do which are just as vital for our research.

Thanks again for all of your help on behalf of all of us using the equipment.”