Differential VHL Mutation Patterns in Bilateral Clear Cell RCC Distinguishes Between Independent Primary Tumors and Contralateral Metastatic Disease

Vocke, Cathy D.; Ricketts, Christopher J.; Metwalli, Adam R.; Pinto, Peter A.; Gautam, Rabindra; Merino, María J.; Ball, Mark W.; Linehan, W. Marston

doi:10.1016/j.urology.2022.04.003

Cited by 3 publications

(3 citation statements)

References 29 publications

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“…One study showed that the spectrum of VHL alterations in bilateral, multifocal ccRCC from a single patient detected by genetic test using NGS will improve the accuracy of differentiation between primary tumors and metastatic disease (14). In this report, we show a case of multifocal ccRCCs with germline translocation, t(3;6)(q12;q14) and differential VHL mutation patterns with a consistent trend of VHL loss that were not detected in the germ line.…”

mentioning

confidence: 62%

Derivative Chromosome 3 Loss from t(3;6)(q12;q14) Followed by DifferentialVHLMutations Underlie Multifocal ccRCC

Mizutani

Yokoi

Sawada

et al. 2022

Cancer Genomics Proteomics

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Background/Aim: The Von Hippel-Lindau (VHL) gene encodes a protein (pVHL) that plays an important role in proteasome degradation of hypoxia inducible factor α (HIFα) through E3 activation. Accumulation of HIFα by loss of functional pVHL promotes tumorigenesis, thus, VHL has tumor suppressor gene capability in clear cell renal cell carcinoma (ccRCC). VHL is the most frequently mutated gene in ccRCC. The complete loss of VHL is mainly achieved by loss of chromosome 3p, which has a VHL coding region in combination with mutation or hypermethylation of the remaining copy of VHL. Given the risk of constitutional chromosome 3 translocation for RCC, it is important to detect the translocation and understand the mechanism underlying the development of multifocal ccRCC. Case Report: A 67year-old female patient diagnosed with multifocal RCC underwent robot-assisted partial nephrectomy (RAPN) for three kidney tumors. A cancer gene panel test using next generation sequencing (NGS) detected differential VHL mutations (c.533T>G; p.L178R, c.465_466insTA; p.T157Ifs*3, c.343C>A; p.H115N), while VHL mutation was not detected in peripheral blood DNA. A tendency toward copy number loss of genes on der(3) was also detected in all tumors, but not in the germline one. A karyotype analysis revealed a germline translocation between 3 and 6, t(3;6)(q12;q14). Conclusion: Chromosome 3 translocation and loss of derivative chromosome containing 3p and subsequent somatic differential VHL mutations in this case strongly support the previously proposed three-step model to explain the development of familial conventional ccRCC.

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mentioning

confidence: 62%

Derivative Chromosome 3 Loss from t(3;6)(q12;q14) Followed by DifferentialVHLMutations Underlie Multifocal ccRCC

Mizutani

Yokoi

Sawada

et al. 2022

Cancer Genomics Proteomics

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“…Recently tumour sequencing studies have demonstrated that some patients presenting with apparent MPRT do in fact have intrarenal metastases from a single primary RCC [14]. Whilst this knowledge has major implications for patient management it seems likely that the frequency of this phenomenon will have been underestimated as tumour sequencing studies are not widely available.…”

Section: Misdiagnosis Of Intrarenal Metastatic Disease As Mprtmentioning

confidence: 99%

“…MPRT may be synchronous or metachronous (the second tumour presents more than 6 months after the first) [10][11][12] and the renal tumours may have the same or different histopathologies [13]. However, the definition of MPRT excludes cases in which there was a single primary renal cancer and intrarenal metastatic secondary tumours [14]. An association between MPRT and inherited renal cancer syndromes such as von Hippel-Lindau (VHL) disease has long been recognised, though in the many cases of MPRT no underlying genetic cause is apparent (for example in a clinical audit of diagnostic testing for a five-gene panel (VHL, FLCN, MET, FH and SDHB) in 39 patients with MPRT without a family history or syndromic features, no pathogenic germline variants were identified (unpublished observations; Andreou A).…”

Section: Introductionmentioning

confidence: 99%

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

Zhang,

Andreou,

Bhatt

et al. 2024

Eur J Hum Genet

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In a subset of patients with renal tumours, multiple primary lesions may occur. Predisposition to multiple primary renal tumours (MPRT) is a well-recognised feature of some inherited renal cancer syndromes. The diagnosis of MPRT should therefore provoke a thorough assessment for clinical and genetic evidence of disorders associated with predisposition to renal tumourigenesis. To better define the clinical and genetic characteristics of MPRT, a systematic literature review was performed for publications up to 3 April 2024. A total of 7689 patients from 467 articles were identified with MPRT. Compared to all patients with renal cell carcinoma (RCC), patients with MPRT were more likely to be male (71.8% versus 63%) and have an earlier age at diagnosis (<46 years, 32.4% versus 19%). In 61.1% of cases MPRT were synchronous. The proportion of cases with similar histology and the proportion of cases with multiple papillary renal cell carcinoma (RCC) (16.1%) were higher than expected. In total, 14.9% of patients with MPRT had a family history of cancer or were diagnosed with a hereditary RCC associated syndrome with von Hippel-Lindau (VHL) disease being the most common one (69.7%), followed by Birt-Hogg-Dubé (BHD) syndrome (14.2%). Individuals with a known or likely genetic cause were, on average, younger (43.9 years versus 57.1 years). In rare cases intrarenal metastatic RCC can phenocopy MPRT. We review potential genetic causes of MPRT and their implications for management, suggest an approach to genetic testing for individuals presenting with MPRT and considerations in cases in which routine germline genetic testing does not provide a diagnosis.

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Inactivation of epithelial sodium ion channel molecules serves as effective diagnostic biomarkers in clear cell renal cell carcinoma

et al. 2023

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Differential VHL Mutation Patterns in Bilateral Clear Cell RCC Distinguishes Between Independent Primary Tumors and Contralateral Metastatic Disease

Cited by 3 publications

References 29 publications

Derivative Chromosome 3 Loss from t(3;6)(q12;q14) Followed by DifferentialVHLMutations Underlie Multifocal ccRCC

Derivative Chromosome 3 Loss from t(3;6)(q12;q14) Followed by DifferentialVHLMutations Underlie Multifocal ccRCC

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

Inactivation of epithelial sodium ion channel molecules serves as effective diagnostic biomarkers in clear cell renal cell carcinoma

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