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

Abstract

Background 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 mRNA profiling. Outcome, measurements and statistical analysis The tumors were segregated into distinct groups according to hierarchical clustering analyses. In addition, the tumors were classified according to luminal, p53-like, and basal categories using previously described algorithm. We applied IPA and GSEA 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 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 which, based on their expression, can be equally divided into luminal and basal subtypes, micropapillary cancer is almost exclusively luminal, displaying enrichment of active PPARγ 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. Conclusions Micropapillary cancer evolves through the luminal pathway and is characterized by the activation of miR-296 and RUVBL1 target genes. Limitations 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. Patient summary Our observations have important implications for prognosis and for possible future development of more effective therapies for micropapillary bladder cancer.

Colon cancer with micropapillary carcinoma component: a clinopathologic study of 9 cases

“…This result may reflect the original clinical behaviour of colon cancer or may not affect the clinical outcome because of the minor component of micropapillary carcinoma. Recently, bladder micropapillary carcinoma was classified as a luminal subtype, a favourable prognosis group in gene expression profile [22]. It is possible that micropapillary carcinoma of the colon may resemble that of the bladder at the molecular genetic level.…”

Evolving concepts of micropapillary variant urothelial carcinoma

“…A particularly interesting finding in the Guo et al study is the fact that when examining tumors with MPV sections and pure urothelial carcinoma sections, the molecular signatures of the urothelial carcinoma sections were similar to the MPV sections (11). This finding would imply that regardless of the percentage of MPV in a tumor specimen, the patient will likely have a more aggressive clinical progression of disease.…”

“…Downregulation of miR-296, which is associated with upregulation of over 300 downstream genes, was found to be a driver in the expression of MPV in the recent study by Guo et al (11). This may be a critical pathway that could be targeted to better identify patients with this uncommon variant of urothelial carcinoma.…”

“…In the recent study by Guo et al, it was reported that whereas in the pure urothelial carcinoma cohort 47.2% were basal subtype, 24.7% were luminal subtype, and 28.1% were p53-like luminal subtype, when examining the MPV urothelial carcinoma cohort, 2.3% were basal subtype (n=1), 51.2% were luminal subtype (n=22), and 46.5% were p53-like luminal subtype (n=20) (11). The MPV urothelial carcinoma tumors demonstrated, almost uniformly, GATA 3 and uroplakin 2.…”

“…The mechanism behind this has been poorly understood. The recent article by Guo et al begins to explore the genetic differences in MPV compared with urothelial carcinoma (11).…”