Gene Expression Profile of the Clinically Aggressive Micropapillary Variant of Bladder Cancer

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• 作者：Charles Chuanhai Guo^a ; ^&dagger ; ; Vipulkumar Dadhania^a ; ^&dagger ; ; Li Zhang^b ; ^&dagger ; ; Tadeusz Majewski^a ; Jolanta Bondaruk^a ; Maciej Sykulski^c ; Weronika Wronowska^d ; Anna Gambin^c ; Yan Wang^a ; Shizhen Zhang^a ; Enrique Fuentes-Mattei^a ; Ashish Madhav Kamat^e ; Colin Dinney^e ; Arlene Siefker-Radtke^f ; Woonyoung Choi^e ; Keith A. Baggerly^b ; David McConkey^e ; John N. Weinstein^b ; Bogdan Czerniak^a ; ^{bczernia@mdanderson.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Micropapillary bladder cancer ; Expression profile ; Molecular signature ; Prognosis
• 刊名：European Urology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：70
• 期：4
• 页码：611-620
• 全文大小：5155 K

文摘

Progression of conventional urothelial carcinoma of the bladder to a tumor with unique microscopic features referred to as micropapillary carcinoma is coupled with aggressive clinical behavior signified by a high propensity for metastasis to regional lymph nodes and distant organs resulting in shorter survival.

Objective

To analyze the expression profile of micropapillary cancer and define its molecular features relevant to clinical behavior.

Design, setting, and participants

We retrospectively identified 43 patients with micropapillary bladder cancers and a reference set of 89 patients with conventional urothelial carcinomas and performed whole-genome expression messenger RNA profiling.

Outcome measurements and statistical analysis

The tumors were segregated into distinct groups according to hierarchical clustering analyses. They were also classified according to luminal, p53-like, and basal categories using a previously described algorithm. We applied Ingenuity Pathway Analysis software (Qiagen, Redwood City, CA, USA) and gene set enrichment analysis for pathway analyses. Cox proportional hazards models and Kaplan-Meier methods were used to assess the relationship between survival and molecular subtypes. The expression profile of micropapillary cancer was validated for selected markers by immunohistochemistry on parallel tissue microarrays.

Results and limitations

We show that the striking features of micropapillary cancer are downregulation of miR-296 and activation of chromatin-remodeling complex RUVBL1. In contrast to conventional urothelial carcinomas that based on their expression can be equally divided into luminal and basal subtypes, micropapillary cancer is almost exclusively luminal, displaying enrichment of active peroxisome proliferator-activated receptor γ and suppression of p63 target genes. As with conventional luminal urothelial carcinomas, a subset of micropapillary cancers exhibit activation of wild-type p53 downstream genes and represent the most aggressive molecular subtype of the disease with the shortest survival. The involvement of miR-296 and RUVBL1 in the development of micropapillary bladder cancer was identified by the analyses of correlative associations of genome expression profiles and requires mechanistic validation.

Conclusions

Micropapillary cancer evolves through the luminal pathway and is characterized by the activation of miR-296 and RUVBL1 target genes.

Patient summary

Our observations have important implications for prognosis and for possible future development of more effective therapies for micropapillary bladder cancer.