Specific Localization of Missense Mutations in the VHL Gene in Clear Cell Renal Cell Carcinoma

Abstract

Missense mutations in the VHL gene during sporadic clear cell renal cell carcinoma were studied to evaluate their localization in relation to functionally important motifs of the VHL protein. Somatic mutations were identified in 124 of 307 samples. All missense mutations in the α-domain were localized in the binding site for elongin C. Substitutions in the β-domain (77%) were found in the HIF-binding site. Five missense mutations were absent in these sites, which illustrates their role in VHL protein formation or suppressor function of other protein cofactors. Mutation c.392A→T (p.N131I) was identified for the first time. Our results hold much promise to estimate the boundaries of functionally important sites in the VHL suppressor gene and contribute to the interpretation of a pathogenic role of mutations in direct DNA diagnostics.

Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma

“…The sophisticated HIF-1α/pVHL system is well-balanced and regulated by different molecular events. First, different missense mutations in the α- and β-domain of the VHL gene cause an altered function of pVHL [ 32 ]. In addition, the accumulation of HIF-1α through loss-of-function mutations or promoter hypermethylation in the VHL gene leads to a dramatic reprogramming of OSCC, due to the prevention of the ubiquitin E3 ligase complex linked degradation [ 20 , 33 ].…”

Spectrum of VHL mutations in clear cell renal cell carcinoma

“…При анализе публикаций выявляются значительные различия в частоте мутаций VHL при скПКРот 41 до 82 % [4,7,11,[16][17][18][19][20][21]. Вариации в частоте мутаций частично связаны с тем, что одни авторы изучают только нон-сайлент-мутации в экзонах, влияющие на структуру белка VHL [21] [18,19]. Изучение связи мутаций VHL с этиологией, прогрессированием и прогнозом скПКР привело к накоплению большого количества противоречивых данных.…”