Differences in VEGFR3 genes between the European and Chinese populations of kidney cancer patients

  Kidney cancer is a common malignant tumor of the genitourinary system, and its incidence has been gradually increasing in recent years. In the past, the main treatment methods for advanced kidney cancer included tumor reduction surgery, radiotherapy, chemotherapy and cytokine therapy, but none of them could achieve satisfactory clinical effects [2-3]. With the application of molecular targeted therapy in tumor treatment, the treatment of advanced kidney cancer has also entered the era of targeted therapy [4]. Sunitinib (Sunitinib) is a novel multi-targeted tyrosine kinase inhibitor that targets and inhibits platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), receptor for stem cell factor (KIT), Fms-like tyrosine kinase 3 receptor (FLT-3), and glial encoded by ret proto-oncogene (RET) cell-derived neurotrophic factor [5], which play a dual role of inhibiting tumor cell proliferation and anti neovascularization. In a phase III clinical study, the median PFS of patients treated with sunitinib was 11 months, with an objective remission rate of 31% [6].       In a phase IV clinical study of advanced kidney cancer in China, the median PFS reached 13.5 months in 105 patients [7]. In clinical practice, some patients were found to be ineffective to targeted therapy, and some others underwent drug reduction or discontinued treatment due to serious adverse effects. Also several studies have found that the incidence of adverse reactions in Asian kidney cancer patients treated with sunitinib is higher than in European and American populations [8-9]. To answer these questions, researchers have endeavored to find factors that can be used to predict the efficacy and tolerability of targeted therapy [10-11]. Many scholars have found a correlation between the appearance of some adverse effects after targeted therapy and prognosis, including hypertension, hand-foot skin reactions, thrombocytopenia, neutropenia, and hypothyroidism [12-15]. However, the objective prediction of efficacy and patient tolerability before treatment initiation is what is urgently needed in clinical work, and currently, single nucleotide polymorphisms in genes related to efficacy and toxic effects are more studied.  SNPs are the most common form of variation in the DNA sequence of human genome, and are considered to be the determinants of disease susceptibility and drug response. In recent years, many scholars have discovered the important role of single nucleotide polymorphisms of certain factors in the pathogenesis in the fields of breast cancer and heart disease [16]. In contrast, in the field of advanced kidney cancer treatment, it was not until 2011 that Lancet Oncol reported the first study on the application of SNPs in advanced kidney cancer patients treated with sunitinib, and its results showed that genetic polymorphisms of VEGFR3 and CYP3A5※1 may be able to identify subgroups of renal cell carcinoma patients with reduced efficacy and tolerance to sunitinib treatment [17]. Subsequently, an increasing number of scholars have conducted studies on the association of SNPs with renal cancer. kim JJ et al. reported that VEGF SNP -634 was associated with the development of hypertension and the combination of VEGF SNP 936 and VEGFR2 SNP 889 genotypes was associated with OS in advanced renal cancer treated with sunitinib in patients with advanced renal cancer [18]. Spanish scholar Sáenz-López et al. looked at the effect of VEGF gene polymorphisms on RCC progression and prognosis in a controlled study of 496 patients, which concluded that there was no significant effect [19]. a controlled study of more than 1000 patients in 2013 showed that the PTPRD rs2279776 SNP might be an aberrant genetic risk factor for kidney cancer [20]. a study by Lee et al. reported that VEGFR1 SNP rs9582036 and rs9554320 were associated with the efficacy of metastatic kidney cancer [21]. a study by Scartozzi et al. showed that VEGF-related SNP loci rs833061, rs699947, rs2010963, and rs6877011 were associated with patients receiving first-line PFS and OS in patients treated with sunitinib [22].A study by Beuselinc et al. found that the SNPs of ABCB1, NR1/2, NR1/3 and VEGFR3 were associated with the efficacy of sunitinib in treating renal cells [23].This scholar also found in another study that the VEGFR1 SNP rs9582036 was associated with sunitinib for renal cell carcinoma efficacy [24].  Several previous studies have found that the distribution of SNPs for a particular gene varies across ethnic groups. In the present study, significant differences were found in the distribution characteristics of SNPs at the VEGFR3 (rs307826) locus and SNPs at the CYP3A5*1 (rs776746) locus between the European and Chinese populations of kidney cancer patients, with a higher proportion of wild-type SNPs at the rs307826 locus of the VEGFR3 gene in the Chinese population, and a higher proportion of wild-type SNPs at the CYP3A5*1 (rs776746) locus in the Chinese population. rs776746) locus SNP heterozygotes were higher in the Chinese population than in the European population, and the distribution characteristics of SNPs were independent of the patients’ gender, age and disease characteristics. The results of studies in both European and Chinese populations suggest that the risk of drug dose reduction due to toxic reactions in targeted therapy is significantly associated with CYP3A5*1. CYP3A5*1 gene polymorphisms affect the expression of CYP3A5 enzyme, which is able to metabolize sunitinib, leading to an increase in the active product and the long-acting metabolite SU12662, producing toxic reactions. The frequency of the CYP3A5*1 allele varies considerably among different ethnic or national groups, and the allele is more commonly found in African and Asian populations, where the frequency of the CYP3A5*1 allele is significantly higher than in European populations, a result that was also confirmed in the present study [25]. This also serves as a potential reason for the higher incidence of toxic side effects in Asian populations treated with sunitinib. Although patients with VEGFR3 (rs307826) SNP wild type were found to be expected to have better outcomes with sunitinib in the European population study, our study found that the proportion of wild type at this Chinese population locus was 99%, which could not be statistically analyzed, which also identified a possible reason for the superior efficacy of sunitinib treatment in Chinese kidney cancer patients compared to the European and American populations.  The results of this study analyzed the distribution characteristics of VEGFR3 gene and CYP3A5*1 gene single nucleotide polymorphisms in the Chinese kidney cancer population, and also confirmed the correlation between CYP3A5*1 gene SNP and the occurrence of toxic side effects of sunitinib, and identified possible reasons for the better efficacy and higher incidence of adverse effects of sunitinib treatment in Chinese kidney cancer patients. These could help us to better understand the molecular mechanisms leading to drug reduction after the application of sunitinib from a pharmacokinetic perspective. This result lays the foundation for the individualized treatment of Chinese kidney cancer patients. Meanwhile, the search for more suitable SNP loci for efficacy prediction in Chinese patients with advanced kidney cancer awaits further clinical studies with large samples.