Cargando…
Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma
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...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10334619/ https://www.ncbi.nlm.nih.gov/pubmed/37434223 http://dx.doi.org/10.1186/s13293-023-00526-7 |
_version_ | 1785070896773332992 |
---|---|
author | Yuan, Huiyang Qin, Xin Yang, Qingya Liu, Li Fang, Zhiqing Fan, Yidong Xu, Dawei |
author_facet | Yuan, Huiyang Qin, Xin Yang, Qingya Liu, Li Fang, Zhiqing Fan, Yidong Xu, Dawei |
author_sort | Yuan, Huiyang |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13293-023-00526-7. |
format | Online Article Text |
id | pubmed-10334619 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-103346192023-07-12 Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma Yuan, Huiyang Qin, Xin Yang, Qingya Liu, Li Fang, Zhiqing Fan, Yidong Xu, Dawei Biol Sex Differ Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13293-023-00526-7. BioMed Central 2023-07-11 /pmc/articles/PMC10334619/ /pubmed/37434223 http://dx.doi.org/10.1186/s13293-023-00526-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Yuan, Huiyang Qin, Xin Yang, Qingya Liu, Li Fang, Zhiqing Fan, Yidong Xu, Dawei Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma |
title | Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma |
title_full | Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma |
title_fullStr | Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma |
title_full_unstemmed | Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma |
title_short | Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma |
title_sort | dyskerin and telomerase rna component are sex-differentially associated with outcomes and sunitinib response in patients with clear cell renal cell carcinoma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10334619/ https://www.ncbi.nlm.nih.gov/pubmed/37434223 http://dx.doi.org/10.1186/s13293-023-00526-7 |
work_keys_str_mv | AT yuanhuiyang dyskerinandtelomerasernacomponentaresexdifferentiallyassociatedwithoutcomesandsunitinibresponseinpatientswithclearcellrenalcellcarcinoma AT qinxin dyskerinandtelomerasernacomponentaresexdifferentiallyassociatedwithoutcomesandsunitinibresponseinpatientswithclearcellrenalcellcarcinoma AT yangqingya dyskerinandtelomerasernacomponentaresexdifferentiallyassociatedwithoutcomesandsunitinibresponseinpatientswithclearcellrenalcellcarcinoma AT liuli dyskerinandtelomerasernacomponentaresexdifferentiallyassociatedwithoutcomesandsunitinibresponseinpatientswithclearcellrenalcellcarcinoma AT fangzhiqing dyskerinandtelomerasernacomponentaresexdifferentiallyassociatedwithoutcomesandsunitinibresponseinpatientswithclearcellrenalcellcarcinoma AT fanyidong dyskerinandtelomerasernacomponentaresexdifferentiallyassociatedwithoutcomesandsunitinibresponseinpatientswithclearcellrenalcellcarcinoma AT xudawei dyskerinandtelomerasernacomponentaresexdifferentiallyassociatedwithoutcomesandsunitinibresponseinpatientswithclearcellrenalcellcarcinoma |