title: TERT promoter mutations are associated with distant metastases in upper tract urothelial carcinomas and serve as urinary biomarkers detected by a sensitive castPCR.
abstract: TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies.
authors.affiliation: Department of Urology, Shandong University Qilu Hospital, Jinan, China. Department of Medicine, Division of Hematology and Centre for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Pathology, Shandong University School of Medicine, Jinan, China.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Urology and Central Research Laboratory, Shandong University Second Hospital, Jinan, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Ge
authors.affiliation: Shandong University School of Nursing, Jinan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Hematology and Centre for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Urology, Shandong University Qilu Hospital, Jinan, China.
authors.forename: Jikai
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Urology and Central Research Laboratory, Shandong University Second Hospital, Jinan, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Kong
authors.affiliation: Department of Medicine, Division of Hematology and Centre for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Chang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Urology, Shandong University Qilu Hospital, Jinan, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Urology, Shandong University Qilu Hospital, Jinan, China.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Yan
authors.affiliation: Department of General Surgery, Shandong University Qilu Hospital, Jinan, China.
authors.forename: Sanyuan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Urology, Shandong University Qilu Hospital, Jinan, China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Medicine, Division of Hematology and Centre for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Björkholm
authors.affiliation: Department of Urology, Shandong University Qilu Hospital, Jinan, China.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Urology and Central Research Laboratory, Shandong University Second Hospital, Jinan, China.
authors.forename: Shengtian
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Urology, Shandong University Qilu Hospital, Jinan, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Hematology and Centre for Molecular Medicine, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden. Department of Urology and Central Research Laboratory, Shandong University Second Hospital, Jinan, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000652:urine*; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology / Q000652:urine; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology / Q000652:urine; D007682:Kidney Pelvis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000175:diagnosis / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics; D012680:Sensitivity and Specificity; D019098:Telomerase / Q000235:genetics*; D014516:Ureteral Neoplasms / Q000235:genetics* / Q000473:pathology / Q000652:urine
chemical_list: D014408:Biomarkers, Tumor; C509186:TERT protein, human; D019098:Telomerase