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.
A 67-year-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).
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.
Cancer genomics & proteomics. 0000 Jan [Epub]
Kosuke Mizutani, Shigeaki Yokoi, Seiya Sawada, Ippei Sakamoto, Koji Kameyama, Shingo Kamei, Kouseki Hirade, Seiji Sugiyama, Kengo Matsunaga, Tetsuya Yamada, Yasutaka Kato, Hiroshi Nishihara, Satoshi Ishihara, Takashi Deguchi
Cancer Genomic Testing and Treatment Center, Central Japan International Medical Center, Minokamo, Japan; ., Department of Urology, Central Japan International Medical Center, Minokamo, Japan., Cancer Genomic Testing and Treatment Center, Central Japan International Medical Center, Minokamo, Japan., Bioinformatics Department, Communication Engineering Center, Electronic Systems Business Group, Mitsubishi Electric Software Corporation, Tokyo, Japan., Department of Pathology, Central Japan International Medical Center, Minokamo, Japan., Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan.