Abstract
Despite major advances in the knowledge of the molecular basis of renal cell carcinoma, prognosis is still defined using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. With these premises, we aimed to analyse the expression and to determine the prognostic and predictive value of 64 key single nucleotide polymorphisms in 18 genes related with angiogenesis or metabolism of antiangiogenics in two cohorts of patients with localized and advanced renal cell cancer treated at our institution. The presence of the selected single nucleotide polymorphisms was correlated with clinical features, disease free survival, overall survival and response rate. In patients with localized renal cell cancer, 5 of these polymorphisms in 3 genes involved in angiogenesis predicted for worse disease free survival (VEGFR2: rs10013228; PDGFRA: rs2228230) or shorter overall survival (VEGFR2: rs10013228; VEGFR3: rs6877011, rs307826) (p < 0.05). Rs2071559 in VEGFR2 showed a protective effect (p = 0.01). In the advanced setting, 5 SNPs determined inferior overall survival (IL8: rs2227543, PRKAR1B: rs9800958, PDGFRB: rs2302273; p = 0.05) or worse response rate (VEGFA: rs699947, rs3025010 p ≤ 0.01)). Additionally 1 single nucleotide polymorphism in VEGFB predicted for better response rate rs594942 (p = 0.03). Genetic analysis of renal cell carcinoma patients might provide valuable prognostic/predictive information. A set of SNPs in genes critical to angiogenesis and metabolism of antiangiogenics drugs seem to determine post-surgical outcomes and treatment response in our series.
Highlights
Renal cell carcinoma (RCC) is the most common malignancy of the kidney with near 338.000 new diagnoses per year worldwide [1]
Our study showed that the presence of certain SPNs was statistically associated with the progression of the disease, the response to treatment and the overall survival in this RCC patient population
Single Nucleotide Polymorphism (SNP) located in these genes could potentially influence the activation of their cognate signaling pathways, which is a well-established mechanism of RCC tumorigenesis
Summary
Renal cell carcinoma (RCC) is the most common malignancy of the kidney with near 338.000 new diagnoses per year worldwide [1]. A better understanding of the molecular biology of RCC has allowed remarkable progress in therapeutics in the last decade This advance comes primarily from the description of the Von Hippel -Lindau (VHL) syndrome; a hereditary condition associated with a mutation in the www.impactjournals.com/oncotarget homonymous tumor suppressor gene, in which around 60% of the patients develop clear cell RCC (ccRCC). Signalling through PDGF promotes cell migration, survival and proliferation and indirectly regulates angiogenesis by inducing transcription and secretion of VEGF [13]. These knowledge and the observation that around 90% of sporadic ccRCC have abnormal function of VHL has led to an intense drug development in RCC targeting VEGF, PDGF or their cognate receptors. More recently other therapeutic strategies such as targeting the program-death 1 (PD-1) receptor or the hepatocyte growth factor receptor (MET) have succeeded [16, 17]
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