Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets

Abstract

Renal cell cancer (RCC) involves three most recurrent sporadic types: clear-cell RCC (70–75%, CCRCC), papillary RCCC (10–15%, PRCC), and chromophobe RCC (5%, CHRCC). Hereditary cases account for about 5% of all cases of RCC and are caused by germline pathogenic variants. Herein, we review how a better understanding of the molecular biology of RCCs has driven the inception of new diagnostic and therapeutic approaches. Genomic research has identified relevant genetic alterations associated with each RCC subtype. Molecular studies have clearly shown that CCRCC is universally initiated by Von Hippel Lindau (VHL) gene dysregulation, followed by different types of additional genetic events involving epigenetic regulatory genes, dictating disease progression, aggressiveness, and differential response to treatments. The understanding of the molecular mechanisms that underlie the development and progression of RCC has considerably expanded treatment options; genomic data might guide treatment options by enabling patients to be matched with therapeutics that specifically target the genetic alterations present in their tumors. These new targeted treatments have led to a moderate improvement of the survival of metastatic RCC patients. Ongoing studies based on the combination of immunotherapeutic agents (immune check inhibitors) with VEGF inhibitors are expected to further improve the survival of these patients.

TRIM7 suppresses cell invasion and migration through inhibiting HIF‐1α accumulation in clear cell renal cell carcinoma

“…ccRCC is the most lethal genitourinary cancer, given that up to one-third of patients present with or develop metastases. Metastatic ccRCC is almost uniformly lethal and biologically distinct from non-metastatic disease (Jonasch et al, 2021;Testa et al, 2020). The mechanisms by which ccRCC evolves into a potentially lethal state have not yet been fully elucidated.…”

“…RCC is a complex disease entity with different histological subtypes, characterized by distinct clinical and pathophysiological features. The most frequent and aggressive subtype is clear cell RCC (ccRCC), which is responsible for approximately 75% of cases (Testa et al, 2020). Although ccRCC can be successfully treated with surgical or ablative strategies if identified early, over 30% of patients present with metastasis at the time of diagnosis (Jonasch et al, 2021).…”

The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis

“…Comprehensive molecular characterization of RCC confirmed the association of VHL gene mutations and the involvement of epigenetic reprogramming in the development of the disease [ 121 , 158 ]. PBRM1, or protein polybromo-1, which is a subunit of ATP-dependent chromatin-remodeling complexes, and SET2D, a histone methyltransferase that specifically trimethylates lysine 36 of histone H3 (H3K36me3), were among the top mutated genes in RCC.…”

Screening of possible biomarkers and therapeutic targets in kidney renal clear cell carcinoma: Evidence from bioinformatic analysis

“…RCC accounts for 4% of adult malignancies. According to the statistics, the probability of males suffering from RCC is 2.2%, and the probability of females suffering from RCC is 1.2% ( 1 ). Most of RCC is originated from renal tubular epithelial cells, accounting for more than 90%.…”