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

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.