Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma.

ABSTRACT

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) displays sex-biased incidence, outcomes, molecular alterations and treatment efficacy; however, clinical managements are largely identical in male and female patients. Moreover, many biomarkers have been identified as predictors for ccRCC outcomes and response to therapeutic drugs, such as multitargeted tyrosine-kinase receptor (TKR) inhibitors, but little is known about their sex-specificity. Dyskerin (DKC1), encoded by the DKC1 gene within Xq28, is a telomerase co-factor stabilizing telomerase RNA component (TERC) and overexpressed in various cancers. Here, we determined whether DKC1 and/or TERC affect ccRCC sex-differentially. METHODS: DKC1 and TERC expression in primary ccRCC tumors was assessed using RNA sequencing and qPCR. DKC1 association with molecular alterations and overall or progression-free survival (OS or PFS) was analyzed in the TCGA cohort of ccRCC. The IMmotion 151 and 150 ccRCC cohorts were analyzed to evaluate impacts of DKC1 and TERC on Sunitinib response and PFS. RESULTS: DKC1 and TERC expression was significantly upregulated in ccRCC tumors. High DKC1 expression predicts shorter PFS independently in female but not male patients. Tumors in the female DKC1-high group exhibited more frequent alterations in PIK3CA, MYC and TP53 genes. Analyses of the IMmotion 151 ccRCC cohort treated with the TKR inhibitor Sunitinib showed that female patients in the DKC1-high group was significantly associated with lower response rates (P = 0.021) accompanied by markedly shortened PFS (6.1 vs 14.2 months, P = 0.004). DKC1 and TERC expression correlated positively with each other, and higher TERC expression predicted poor Sunitinib response (P = 0.031) and shorter PFS (P = 0.004), too. However, DKC1 rather than TERC acted as an independent predictor (P < 0.001, HR = 2.0, 95% CI 1.480-2.704). In male patients, DKC1 expression was associated with neither Sunitinib response (P = 0.131) nor PFS (P = 0.184), while higher TERC levels did not predict response rates. Similar results were obtained from the analysis of the Sunitinib-treated IMmotion 150 ccRCC patients. CONCLUSIONS: DKC1 serves as an independent female-specific predictor for survival and Sunitinib efficacy in ccRCC, which contribute to better understanding of the sex-biased ccRCC pathogenesis and improve personalized interventions of ccRCC.

Many types of cancer including clear cell renal cell carcinoma (ccRCC) are known to display sex-biased survival, genomic alterations and treatment efficacy; however, clinical managements are largely identical in male and female ccRCC patients. Many molecules have been identified as predictors for ccRCC survival and response to therapeutic drugs, such as multitargeted tyrosine-kinase receptor inhibitor Sunitinib, but little is known about their sex-specificity. Dyskerin (DKC1), encoded by the DKC1 gene on X chromosome, is a telomerase co-factor stabilizing telomerase RNA component (TERC), whereas telomerase plays key roles in cancer development and progression. In this study, we observed increased DKC1 expression in ccRCC tumors. High DKC1 expression predicts shorter disease progression-free survival (PFS) in female but not male patients. Oncogene activation and tumor suppressor inactivation are more frequent in the female DKC1-high tumors. By analyzing two cohorts of ccRCC patients treated with Sunitinib, we showed that female patients in the DKC1-high group was significantly associated with lower response rates accompanied by markedly shortened PFS. DKC1 and TERC expression correlated positively with each other, and higher TERC expression predicted poor Sunitinib response and shorter PFS, too. However, DKC1 rather than TERC acted as an independent predictor. In male patients, DKC1 expression was associated with neither Sunitinib response nor PFS. Thus, DKC1 serves as a female-specific predictor for survival and Sunitinib response in ccRCC. Our findings are expected to improve personalized management of ccRCC.