Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine.
What's known on the subject? and What does the study add? Sporadic clear cell Renal Cell Carcinoma (ccRCC) is dominated by nutations of the VHL gene located on chromosome 3p in up to 90% of cases. This gene plays a critical role in hypoxia response, including stimulation of neoangiogenesis. Since 2006, anti-angiogenci therapies targeting this pathway are used in metastatic patients with objective response rate as high as 45%. However, these treatments don't target directly the tumour cell, allowing the potential for disease progession despite treatment. Large scale analysis recently showed that substantial genetic heterogeneity exists in ccRCC. Associated alterations include genes implicated in methylation regulation in 15% of cases, underlying the importance of epigenetic modifications, and truncating mutations in chromatin remodelling complex PRMB1 in 41% of cases. Systematic screening of these tumours is a way to fully determine the somatic genetic architecture of RCC in order to improve tumour classification, to develop prognostic and predictive markers and to target new molecular pathways involved in carcinogenesis. • A critical review is provided of the recent progress in oncogenetics applied to renal cell carcinoma (RCC) by highlighting our current understanding of the genetic pathways involved in carcinogenesis and its current and future clinical application. • RCC comprises a model of translational research because an improved understanding of molecular pathways has led to several targeted therapy options for patients with metastatic RCC. • Alteration of the product of the Von Hippel-Lindau gene/hypoxia inductible factor/vascular endothelial growth factor pathway is well characterized in carcinogenesis and is the target of the current therapies for metastatic RCC. • However, substantial genetic heterogeneity exists in this cancer and current treatments do not target directly the tumour cell. • Improving overall survival still remains a challenging objective but, currently, there is a lack of prognostic and predictive biomarkers for response to treatment. • Further information is awaited from the genomic approach to tumour classification, prognostic markers and predictive indicators of response to the treatment, as well as the personal susceptibility of developing RCC when exposed to risk factors. • Recent technological developments, such as large-scale analysis and high-speed sequencing, will allow the systematic screening of tumours to fully determine the somatic genetic architecture of RCC.
The Academic Department of Urology of La Pitié-Salpétrière and of Tenon, Groupe Hospitalo-Universitaire Est, Assistance-Publique Hôpitaux de Paris Faculté , Paris, France.
François
F
Audenet
David R
DR
Yates
Géraldine
G
Cancel-Tassin
Olivier
O
Cussenot
Morgan
M
Rouprêt
D014408:Biomarkers, Tumor / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D023281:Genomics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics*; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D057285:Precision Medicine / Q000379:methods; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases