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| Gene Symbol | VHL | ||||||||||
| Synonyms | HRCA1 | pVHL | RCA1 | VHL1 | ||||||||||
| Gene Description | VHL, von Hippel-Lindau tumor suppressor, is part of an E3 ubiquitin protein ligase complex, which promotes degradation of HIF-alpha and other protein targets required for cellular growth and angiogenesis (PMID: 24583008, PMID: 30194449), and plays a role in genomic stability (PMID: 31747945). VHL contributes to von Hippel-Lindau disease (PMID: 30194449, PMID: 30006056) and sporadic tumors, including clear cell renal carcinoma (PMID: 24583008, PMID: 30149673). | ||||||||||
| ACMG Incidental List v3.0: |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| VHL negative | renal cell carcinoma | sensitive | STF-62247 | Preclinical | Actionable | In a preclinical study, STF-62247 induced selective cytotoxicity and inhibited tumor growth of renal cell carcinoma cells lacking VHL (PMID: 18769110, PMID: 18598947). | 18769110 18598947 |
| VHL mutant | renal cell carcinoma | sensitive | Everolimus | Phase I | Actionable | In a Phase I study, Afinitor (everolimus), as compared to Apitolisib (GDC-0980), resulted in a greater progression free survival and overall survival in patients with renal cell carcinoma harboring VHL mutations (J Clin Oncol 32:5s, 2014 (suppl; abstr 4525)). | detail... |
| VHL mutant | renal cell carcinoma | predicted - sensitive | Sunitinib | Phase I | Actionable | In a Phase I trial, 33% (6/18) of renal cell carcinoma patients harboring a VHL mutation, as determined from archived patient specimens, demonstrated a partial response when treated with Sutent (sunitinib) (PMID: 22105611). | 22105611 |
| VHL mutant | islet cell tumor | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with well-differentiated Grade 1/2 progressive pancreatic neuroendocrine tumors harboring germline VHL mutations (NCCN.org). | detail... |
| VHL mutant | renal cell carcinoma | no benefit | Unspecified VEGFR inhibitor | Clinical Study - Meta-analysis | Actionable | In a meta-analysis of 6 clinical studies, VHL mutation status was not associated with overall response rate (relative risk=1.47, p=0.20), progression-free survival (HR=1.02, p=0.91), or overall survival (HR=0.80, p=0.21) in a total of 633 patients with renal cell carcinoma who received anti-VEGF therapies (PMID: 28103578). | 28103578 |
| VHL inact mut | renal cell carcinoma | predicted - sensitive | Everolimus | Case Reports/Case Series | Actionable | In a retrospective analysis from a Phase II clinical trial, patients with metastatic renal cell carcinoma treated with Afinitor (everolimus) had a trend towards improved in progression-free survival when stratified by the presence (median PFS=8.6 months, n=15) or absence (median PFS=5.5 months, n=16) of deleterious VHL mutations (PMID: 26951309). | 26951309 |
| VHL inact mut | renal cell carcinoma | no benefit | Apitolisib | Case Reports/Case Series | Actionable | In a retrospective analysis from a Phase II clinical trial, patients with metastatic renal cell carcinoma treated with Apitolisib (GDC-0980) had no difference in progression-free survival when stratified by the presence (n=5) or absence (n=17) of deleterious VHL mutations (PMID: 26951309). | 26951309 |
| VHL inact mut | renal cell carcinoma | sensitive | Pazopanib | Phase II | Actionable | In a Phase II trial, Votrient (pazopanib) treatment resulted in an objective response rate of 42% (13/31, 13 partial responses) and stable disease in 58% of patients with Von Hippel-Lindau disease, with 75% (24/32) of the patients harboring confirmed VHL mutations; 52% (31/59, 2 complete and 29 partial responses) of target renal cell carcinomas responded to the treatment (PMID: 30236511; NCT01436227). | 30236511 |
| VHL inact mut | renal cell carcinoma | sensitive | Pazopanib | Guideline | Actionable | Votrient (pazopanib) is included in guidelines as systemic therapy for patients with renal cell carcinoma associated with Von Hippel-Lindau disease (NCCN.org). | detail... |
| VHL inact mut | islet cell tumor | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in VHL result in von Hippel-Lindau (VHL) syndrome, which is associated with increased risk of developing pancreatic neuroendocrine tumors (NCCN.org). | detail... |
| VHL inact mut | clear cell renal cell carcinoma | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in VHL result in von Hippel-Lindau (VHL) syndrome, which is associated with increased risk of developing clear cell renal cell carcinoma (NCCN.org). | detail... |
| VHL inact mut | renal cell carcinoma | predicted - sensitive | Alpha 2 Interferon + Bevacizumab | Clinical Study - Cohort | Actionable | In a retrospective analysis, VHL alterations did not impact overall survival or objective response in renal cell carcinoma patients treated with a VEGF-targeted therapy, including Avastin (bevacizumab) and Alpha 2 Interferon combination therapy, but were associated with a prolonged time to progression (PMID: 16827904). | 16827904 |
| VHL inact mut | clear cell renal cell carcinoma | conflicting | PT2399 | Preclinical - Pdx | Actionable | In a preclinical study, PT2399 had variable impact on tumor growth in clear cell renal cell carcinoma (ccRCC) cell line and patient-derived xenograft (PDX) models with defective VHL, with decreased tumor growth in a VHL-defective ccRCC PDX model and some VHL-defective ccRCC cell line xenograft models, and no tumor suppression in other cell line xenograft models (PMID: 27595393). | 27595393 |
| VHL inact mut | pancreatic endocrine carcinoma | sensitive | Belzutifan | FDA approved | Actionable | In a Phase II trial that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in an overall response rate of 80% (16/20, 1 complete response, 15 partial responses) in patients with Von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors harboring germline VHL mutations (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). | detail... detail... |
| VHL inact mut | renal cell carcinoma | sensitive | Belzutifan | FDA approved | Actionable | In a Phase II trial that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in a confirmed partial response (PR) in 36% (22/61) and unconfirmed PR in 11% (7/61) of patients with Von Hippel-Lindau disease-associated localized renal cell carcinoma harboring germline VHL mutations, median duration of response was not reached in responders (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). | detail... detail... |
| VHL inact mut | renal cell carcinoma | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with Von Hippel-Lindau disease-associated renal cell carcinoma that do not require immediate surgery (NCCN.org). | detail... |
| VHL inact mut | retinal hemangioblastoma | sensitive | Belzutifan | Phase II | Actionable | In a Phase II trial, Welireg (belzutifan) treatment was safe and resulted in an overall response rate of 32% (16/50, 1 complete response, 15 partial responses) in patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma harboring germline VHL mutations, 69% (11/16) of patients with retinal hemangioblastoma experienced improvement (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). | detail... |
| VHL inact mut | hemangioblastoma | sensitive | Belzutifan | FDA approved | Actionable | In a Phase II trial (LITESPARK-004) that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in an objective response rate of 44% (22/61, 4 complete responses, 18 partial responses) in patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma harboring germline VHL mutations, with a disease control rate of 90%, a median time to response of 5.4 months, and median progression-free survival not reached (J Clin Oncol 41, 2023 (suppl 16; abstr 2008); NCT03401788). | detail... detail... |
| VHL inact mut | hemangioblastoma | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma that do not require immediate surgery (NCCN.org). | detail... |
| TP53 R248W VHL inact mut | clear cell renal cell carcinoma | resistant | PT2399 | Preclinical - Cell culture | Actionable | In a preclinical study, TP53 R248W was associated with resistance to PT2399 in VHL-defective clear cell renal cell carcinoma cell lines in culture (PMID: 27595393). | 27595393 |
| TP53 wild-type VHL inact mut | renal cell carcinoma | sensitive | M8891 + Sunitinib | Preclinical - Pdx | Actionable | In a preclinical study, M8891 and Sutent (sunitinib) combination treatment resulted in improved tumor growth inhibition compared to monotherapies in patient-derived xenograft (PDX) models of TP53 wild-type renal cell carcinoma harboring VHL inactivating mutations (PMID: 37940144). | 37940144 |
| TP53 wild-type VHL inact mut | renal cell carcinoma | sensitive | Cabozantinib + M8891 | Preclinical - Pdx | Actionable | In a preclinical study, M8891 and Cometriq (Cabometyx, cabozantinib) combination treatment resulted in improved tumor growth inhibition compared to monotherapies in patient-derived xenograft (PDX) models of TP53 wild-type renal cell carcinoma harboring VHL inactivating mutations (PMID: 37940144). | 37940144 |
| TP53 wild-type VHL inact mut | renal cell carcinoma | sensitive | Axitinib + M8891 | Preclinical - Pdx | Actionable | In a preclinical study, M8891 and Inlyta (axitinib) combination treatment resulted in improved tumor growth inhibition compared to monotherapies in patient-derived xenograft (PDX) models of TP53 wild-type renal cell carcinoma harboring VHL inactivating mutations (PMID: 37940144). | 37940144 |
| VHL loss | renal cell carcinoma | sensitive | Bevacizumab | Preclinical | Actionable | In a preclinical study, clear cell renal cell carcinoma xenograft models with VHL loss demonstrated sensitivity to Avastin (bevacizumab) (PMID: 22931246). | 22931246 |
| VHL loss | renal cell carcinoma | sensitive | Telaglenastat | Preclinical - Cell culture | Actionable | In a preclinical study, VHL-deficient renal cell carcinoma cells demonstrated growth inhibition in culture when treated with CB-839 (PMID: 28346230). | 28346230 |
| VHL loss | renal cell carcinoma | sensitive | ELR510444 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, renal cell carcinoma cells deficient for VHL were sensitive to ELR510444 both in culture and in cell line xenograft models (PMID: 22295124). | 22295124 |
| VHL loss | renal cell carcinoma | sensitive | BPTES | Preclinical - Cell culture | Actionable | In a preclinical study, VHL-deficient renal cell carcinoma cells demonstrated growth inhibition and suppression of DNA synthesis in culture when treated with BPTES (PMID: 28346230). | 28346230 |
| VHL loss | renal cell carcinoma | sensitive | Olaparib + Telaglenastat | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of CB-839 and Lynparza (olaparib) resulted in a synergistic effect, demonstrating greater reduction in tumor volume compared to either agent alone in renal carcinoma cell xenograft models deficient for VHL (PMID: 28346230). | 28346230 |
| VHL loss | renal cell carcinoma | sensitive | BPTES + Olaparib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of BPTES and Lynparza (olaparib) resulted in a synergistic effect, demonstrating growth inhbition of VHL-deficient renal cell carcinoma cells in culture (PMID: 28346230). | 28346230 |
| PTEN loss VHL loss | renal carcinoma | decreased response | Gedatolisib | Preclinical | Actionable | In a preclinical study, human renal carcinoma cells with PTEN loss and VHL loss had a decreased response to Gedatolisib (PKI-587) in culture (PMID: 21325073). | 21325073 |
| VHL S111R | leukemia | resistant | ARV-771 | Preclinical - Cell culture | Actionable | In a preclinical study, a leukemia cell line demonstrated resistance to ARV-771 and was found to have acquired VHL S111R in culture (PMID: 36329119). | 36329119 |
| VHL over exp | clear cell renal cell carcinoma | no benefit | Cediranib + Saracatinib | Phase II | Actionable | In a Phase II clinical study, baseline expression of VHL was not predictive for response to Saracatinib (AZD0530) and Recentin (cediranib) relative to Recentin (cediranib) in patients with metastatic clear-cell renal cell carcinoma (PMID: 26802156). | 26802156 |
| VHL del | renal cell carcinoma | predicted - sensitive | Regorafenib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Stivarga (regorafenib) inhibited angiogenesis and tumor growth in cell line xenograft models of renal cell carcinoma harboring VHL gene deletion (PMID: 21170960). | 21170960 |
| VHL V155fs | kidney cancer | predicted - sensitive | Sunitinib + Trametinib | Preclinical - Pdx | Actionable | In a preclinical study, the combination of Mekinist (trametinib) and Sutent (sunitinib) inhibited tumor growth in patient-derived xenograft models of renal cancer harboring VHL V155fs (referred to as V155fs*4) (PMID: 26487278). | 26487278 |
| VHL Y112C | leukemia | resistant | ARV-771 | Preclinical - Cell culture | Actionable | In a preclinical study, a leukemia cell line demonstrated resistance to ARV-771 and was found to have acquired VHL Y112C in culture (PMID: 36329119). | 36329119 |
| VHL Y112C | colon carcinoma | resistant | ARV-771 | Preclinical - Cell culture | Actionable | In a preclinical study, a colon carcinoma cell line expressing VHL Y112C was resistant to ARV-771 in culture (PMID: 36329119). | 36329119 |
| VHL W117* | leukemia | resistant | ARV-771 | Preclinical - Cell culture | Actionable | In a preclinical study, a leukemia cell line demonstrated resistance to ARV-771 and was found to have acquired VHL W117* in culture (PMID: 36329119). | 36329119 |
| VHL V166F | leukemia | resistant | ARV-771 | Preclinical - Cell culture | Actionable | In a preclinical study, a leukemia cell line demonstrated resistance to ARV-771 and was found to have acquired VHL V166F in culture (PMID: 36329119). | 36329119 |
| VHL S139fs | leukemia | resistant | ARV-771 | Preclinical - Cell culture | Actionable | In a preclinical study, a leukemia cell line demonstrated resistance to ARV-771 and was found to have acquired VHL S139fs in culture (PMID: 36329119). | 36329119 |
| VHL H110L | colon carcinoma | sensitive | ARV-771 | Preclinical - Cell culture | Actionable | In a preclinical study, ARV-771 inhibited viability in a colon carcinoma cell line expressing VHL H110L in culture (PMID: 36329119). | 36329119 |
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