Abstract
We aimed to analyze genotypes of VEGF-A, VEGFR2, Flt4, PDGFRα, HIF-1α and ERCC1 and their correlation with thymic tumor risk and patient outcome. DNA of 57 consecutive patients (43 thymomas and 14 thymic carcinomas) who underwent total thymectomy at our Institution was extracted from paraffin-embedded tissue. We selected polymorphisms in the following genes:HIF1-α (rs2057482T > C, rs1951795A > C, rs2301113C > A, rs10873142C > T, rs11158358G > C, rs12434438G > A, rs11549465C > T, rs11549467G > A), VEGF-A (rs2010963G > C, rs699947A > C), VEGFR-2 (rs2305948C > T, rs1870377T > A), VEGFR-3 (rs307826T > C, rs307821C > A), PDGFR-α (rs35597368C > T) and ERCC1 (rs11615A > G). Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. As compared to the general population, the allele frequency of PDGFR-α rs35597368T was significantly higher (95% vs. 87%, p = 0.036), while the frequency of alleles HIF1-α rs2057482C (78% vs. 90%), rs1951795C (69% vs. 87%), rs2301113A (70% vs. 83%), rs10873142T (70% vs. 87%), rs11158358C (75% vs. 88%), rs12434438A (67% vs. 84%) were significantly lower. VEGFR-3 rs307821C frequency was significantly higher in thymomas vs. thymic carcinomas (79% vs. 72%, p = 0.0371). The following factors were significantly correlated with a longer overall survival: VEGFR-3 rs307826C, VEGFR-2 rs1870377A, PDGFR-α rs35597368T/C, HIF1-α rs2301113C, rs2057482C/T, rs1951795C, rs11158358G/C and rs10873142T/C, ERCC1 rs11615A (p < 0.05). Our results suggest, for the first time, that PDGFR-α, HIF-1α and VEGFR-3 SNPs are associated with thymic cancer risk and survival.
Highlights
Thymic epithelial tumors (TETs) are rare malignancies with an overall annual incidence of 0.15 per 100.000 inhabitants
For the first time, that PDGFR-α, Hypoxia-inducible factor-1α (HIF-1α) and VEGFR-3 SNPs are associated with thymic cancer risk and survival
Fifty-seven patients with TETs were included in this study: 43 (75%) presented with thymoma and 14 (25%) with thymic carcinomas (TC)
Summary
Thymic epithelial tumors (TETs) are rare malignancies with an overall annual incidence of 0.15 per 100.000 inhabitants. Emerging data indicate that thymomas and thymic carcinomas (TC) are distinct entities, characterized by peculiar anatomical and clinical features, biological behavior, gene expression and sequencing data. Despite several advances in molecular biology are shedding light onto the variety of genetic aberrations involved in thymic carcinogenesis, our current understanding still remain limited. Vascular endothelial growth factor-A (VEGF-A) and its receptors (VEGFR1 and VEGFR2) are implicated in regulating physiological and pathological angiogenesis. VEGF-A has been proposed as a proangiogenic and autocrine factor in thymomas and as an immunoregulatory factor in the normal thymus. [5] Both VEGF-A and VEGFRs are overexpressed in TETs compared to normal thymus and seem to be associated with advanced clinical stages, predominantly in TC. VEGF-A has been proposed as a proangiogenic and autocrine factor in thymomas and as an immunoregulatory factor in the normal thymus. [5] Both VEGF-A and VEGFRs are overexpressed in TETs compared to normal thymus and seem to be associated with advanced clinical stages, predominantly in TC. [6]
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