Methylation of SPARCL1 Is Associated with Oncologic Outcome of Advanced Upper Urinary Tract Urothelial Carcinoma.

Hao-Lun Luo,Po-Huang Chiang,Chun-Chieh Huang,Chang-Shen Lin,Eing-Mei Tsai,Po-Hui Chiang,Yu-Li Su,Min-Tse Sung

doi:10.3390/ijms20071653

Abstract

Advanced upper urinary tract urothelial carcinoma (UTUC) is often associated with poor oncologic outcomes. The secreted protein acidic and rich in cysteine-like 1 (SPARCL1) protein, belongs to the SPARC-related family of matricellular proteins. Much literature has been published describing the role of SPARCL1 in the prognosis many cancers. In this study, methylated promoter regions in high-grade and high-stage upper urinary urothelial tumours compared with normal urothelium were analyzed and revealed that SPARCL1 was the most significantly hypermethylated gene in UTUC tissues. Then we prospectively collected UTUC samples and adjacent normal urothelium for pyrosequencing validation, identifying significant CpG site methylation in UTUC tissues. In addition, SPARCL1 RNA levels were significantly lower in UTUC samples. Multivariate Cox regression analysis from 78 patients with solitary renal pelvic or ureteral pT3N0M0 urothelial carcinomas revealed that only negative SPARCL1 expression and nonpapillary tumour architecture were independently associated with systemic recurrence (p = 0.011 and 0.008, respectively). In vitro studies revealed that the behaviour of BFTC-909 cells was less aggressive and more sensitive to radiation or chemotherapy after SPARCL1 overexpression. Thus, SPARCL1 could be considered as a prognostic marker and help decision-making in clinical practice.

Highlights

Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare disease compared with urinary bladder urothelial carcinoma
We found that high-stage/high-grade UTUC samples had significant SPARCL1 hypermethylation compared with normal urothelium adjacent to low-stage/low-grade specimens
The top 10 hypermethylated genes are shown in Figure 1C; SPARCL1 hypermethylation was found to be increased 20-fold in UTUC tissue (p = 4 × 10−5)

Summary

Introduction

Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare disease compared with urinary bladder urothelial carcinoma. Advanced UTUC is often associated with poor oncologic outcome [1]. Chemotherapy is the current standard therapy for advanced UTUC in the neoadjuvant or adjuvant setting [2]. The high prevalence of renal insufficiency in UTUC is a clinical challenge [3]. For those patients with renal insufficiency, which means they are ineligible for chemotherapy, radiation therapy is sometimes an adjunct strategy. Further exploration of treatment targets sensitive to treatment multimodality may help improve clinical outcome

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