The Clinical and Molecular Features in the VHL Renal Cancers; Close or Distant Relatives with Sporadic Clear Cell Renal Cell Carcinoma?

Abstract

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer syndrome caused by germline mutations in the VHL tumor suppressor gene, characterized by the susceptibility to a wide array of benign and malign neoplasms, including clear-cell renal cell carcinoma. Moreover, VHL somatic inactivation is a crucial molecular event also in sporadic ccRCCs tumorigenesis. While systemic biomarkers in the VHL syndrome do not currently play a role in clinical practice, a new promising class of predictive biomarkers, microRNAs, has been increasingly studied. Lots of pan-genomic studies have deeply investigated the possible biological role of microRNAs in the development and progression of sporadic ccRCC; however, few studies have investigated the miRNA profile in VHL patients. Our review summarize all the new insights related to clinical and molecular features in VHL renal cancers, with a particular focus on the overlap with sporadic ccRCC.

Hereditary Renal Cancer Syndromes

“…In addition, a number of small-molecule multikinase inhibitors (sunitinib, axitinib, pazopanib, cabozantinib, etc. ), which are often marketed as antiangiogenic drugs, have been incorporated into the treatment standards for metastatic RCCs [93]. The development of belzutifan (previously called MK-6482 or PT2977), an allosteric inhibitor of HIF2alpha, led to a breakthrough in the treatment of RCCs arising in VHL germline mutation carriers [94,95].…”

“…Von Hippel-Lindau disease Antiangiogenic therapy and multikinase inhibitors; "Watch-and-wait" approach (lesions < 3 cm in diameter) [82] Anti-HIF2-alpha therapy (belzutifan) [93][94][95][96] Fumarate hydratase deficiency Bevacizumab + erlotinib; multikinase inhibitors; immune therapy [97][98][99][100][101][102][103][104][105] Immediate surgical removal [106] Hereditary pheochromocytoma/ paraganglioma syndrome Immediate surgical removal [72] Hereditary papillary renal cell carcinoma MET inhibitors (crizotinib, capmatinib) [107][108][109] "Watch-and-wait" approach (lesions < 3 cm in diameter) [71,110] Birt-Hogg-Dubé Syndrome mTOR inhibitors (everolimus)? [111] "Watch-and-wait" approach (lesions < 3 cm in diameter) [106] Tuberous sclerosis mTOR inhibitors (everolimus) [112][113][114] "Watch-and-wait" approach for angiomyolipomas, insufficient evidence regarding RCC [115,116] BAP1 tumor predisposition syndrome Insufficient evidence, but immediate surgical removal is suggested [106] Cowden syndrome mTOR inhibitors (everolimus)?…”

The Crucial Findings Derived from the Special Issue “Inside Cancer Genomics: From Structure to Therapy”

“…Cinque et al [ 36 ] summarize, in a review, the clinical spectrum and molecular features of an autosomal dominant inherited cancer syndrome, Von Hippel-Lindau (VHL) disease, in order to highlight new molecular opportunities based on genetic alterations, biological pathways, and potential biomarkers.…”