Abstract
The long non-coding RNA (lncRNA) H19 has been demonstrated to play a crucial role in carcinogenesis, including renal cell carcinoma (RCC). However, the impact of genetic variations in H19 gene on RCC has not been investigated before. In the present study, we sought to evaluate whether genetic polymorphisms in H19 are related to the susceptibility and mortality of RCC. We genotyped four widely studied polymorphisms in H19 and assessed their relationship with susceptibility and prognosis of RCC in a case-control study compromising 1,027 cases and 1,094 controls. The functionality of the important polymorphism was further investigated by real-time polymerase chain reaction and luciferase reporter assay. We found that H19 rs2839698 was significantly associated with risk and prognosis of RCC. Compared with the H19 rs2839698 CC genotype, the variant genotypes (CT/TT) were significantly associated with increased risk of RCC (P = 0.023, OR = 1.21; 95% CI = 1.03–1.45). Besides, patients with variant genotypes (CT/TT) were more likely to develop large tumor (P = 0.003, OR = 1.47; 95% CI = 1.16–1.85) and advanced disease (P = 0.010, OR = 1.59; 95% CI = 1.12–2.26); and had a significantly unfavorable overall survival than those with the rs2839698 CC genotype (CT/TT vs. CC: Log-rank P = 0.026, HR = 2.25, 95%CI = 1.07–4.75). Furthermore, the CT/TT genotypes were associated with significantly increased expression of H19 in renal tissue. The luciferase reporter assays revealed the potential effect of rs2839698 variant on the binding of microRNAs to H19. Our results suggest that the H19 rs2839698 variant may be a genetic predictor of susceptibility and mortality of RCC. The risk effects and the functional impact of the variant on H19 still need further validation.
Highlights
Renal cell carcinoma (RCC) is the predominant type of kidney cancer, accounting for 5 and 3% of all malignancies in men and women, respectively [1, 2]
We investigated the associations between polymorphisms in H19 and renal cell carcinoma (RCC) susceptibility as well as prognosis in a Chinese population
Our results suggested that the H19 rs2839698 variant was associated with an increased risk of RCC
Summary
Renal cell carcinoma (RCC) is the predominant type of kidney cancer, accounting for 5 and 3% of all malignancies in men and women, respectively [1, 2]. Genetic variations have been widely studied and demonstrated to influence the susceptibility, progression and prognosis of RCC [6,7,8]. Accumulating evidence suggests that lncRNAs play a crucial role in the occurrence and progression of various type of cancer [10, 11]. LncRNA H19 is a paternally imprinted gene which is located in chromosome 11p15.5 in human [12], and participates in numerous important biological and pathological processes through regulating the function of miRNAs [13] and mediating the DNA methylation [14]. H19 is closely linked to insulin-like growth factor-2 (IGF2) gene which is located in the region subjected to imprinting by methylation and plays a crucial role in the normal growth and development of the fetus [15] and important in cancer occurrence and progression [16]. The expression of lncRNA H19 was proposed to be an independent predictor for the clinical outcome of RCC patients [20]
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