Published Articles  from the 100,000 genomes project VHL study

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}