Genetic variants in a long noncoding RNA related to Sunitinib Resistance predict risk and survival of patients with renal cell carcinoma

Abstract

Objective LncARSR (lncRNA Activated in RCC with Sunitinib Resistance, ENST00000424980) is a newly identified lncRNA to promote the sunitinib resistance of renal cell carcinoma (RCC), which may contribute to tumorigenesis and progression. This study aimed to explore the association of lncARSR tagSNPs with the risk and prognosis of RCC. Methods In this study, a 2‐stage case‐control study was performed to evaluate the association between 2 tagging SNPs (rs1417080 and rs7859384) and RCC susceptibility. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained by unconditional logistic regression analyses. Different survival time was estimated by the Kaplan‐Meier method and compared by the Log‐rank test. Hazard ratios (HRs) and their 95% CIs were calculated to determine predictive factors by Cox proportion hazards model. Results When combing discovery and validation sets together, rs7859384 was determined to be significantly associated with the decreased RCC risk with all P < 0.05 in 4 models (co‐dominant model, additive model, dominant model and recessive model). stratified analyses showed prominent risk effect of SNP rs7859384 GA/GG genotypes was found in clinical subgroups of stage I and stage II (P = 0.009, OR = 0.77, 95% CI = 0.64‐0.94) and individuals with clear cell RCC (P = 0.014, OR = 0.79, 95% CI = 0.65‐0.95). A protective effect of SNP rs7859384 GA/GG genotypes was observed among individuals with BMI > 24 (P = 0.025, OR = 0.74, 95% CI = 0.56‐0.96), without hypertension (P = 0.037, OR = 0.79, 95% CI = 0.63‐0.99), without family history of cancer (P = 0.048, OR = 0.83, 95% CI = 0.68‐1.00). Survival analyses revealed individuals with GA/GG genotypes had higher survival rate compared with the corresponding AA wild genotypes in the dominant model (log‐rank P = 0.005, adjusted HR = 0.34, 95% CI = 0.16‐0.73). Conclusion This study suggests that rs7859384 of lncARSR was associated with RCC susceptibility and may act as a prognostic biomarker for patients with RCC.

lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System

“…Moreover, pretreatment ARSR levels in the plasma of RCC patients is significantly correlated with poor PFS for high vs. low ARSR expression (HR = 2.9, 95% CI = 1.2-7.1, p = 0.017), corroborating these findings [16]. A recent study also proposed single nucleotide polymorphisms (SNP) of the ARSR sequence as potential biomarkers for RCC outcome [64].…”

Evaluation and Application of Drug Resistance by Biomarkers in the Clinical Treatment of Liver Cancer

“…This upregulation of the PTEN-PI3K/AKT pathway by elevated lncARSR expression underlies doxorubicin resistance in HCC, as evidenced by the fact that inhibition of the PI3K/AKT pathway abolishes lncARSR-dependent doxorubicin resistance in HCC cells, and depletion of PTEN reverses the effects of lncARSR knockdown on doxorubicin resistance in HCC cells [ 71 ]. It is important to note that lncARSR has been found to cause resistance to sunitinib and adriamycin in renal cell carcinoma and osteosarcoma [ 72 , 73 ].…”

LncRNA polymorphisms and urologic cancer risk

“…People with the GA/GG genotypes showed a greater survival rate than those with the AA wild genotypes under the dominant model (adjusted HR = 0.34). Their findings imply that rs7859384 of the lncARSR gene is linked to RCC susceptibility and might be used as a predictive biomarker for RCC patients (Xing et al, 2019).…”

“…Furthermore, lncARSR has been shown to alter the proliferation of renal tumo-inducing cells that might help tumorigenesis, progression, and treatment resistance (Qu, Ding, et al, 2016;. Furthermore, via modulating the Akt/SREBP2/ HMGCR pathway, lncARSR may alter hepatic lipogenesis and cause hepatic cholesterol biosynthesis (Huang, Chen, et al, 2018) of the lncARSR gene is linked to RCC susceptibility and might be used as a predictive biomarker for RCC patients (Xing et al, 2019).…”