Bladder Cancer: New Insights into Its Molecular Pathology

Kentaro Inamura, Kentaro Inamura

Abstract

Bladder cancer is one of the most prevalent cancers worldwide. Unfortunately, there have been few advances in its clinical management due to a poor understanding of the correlations between its molecular and clinical features. Mounting evidence suggests that bladder cancer comprises a group of molecularly heterogeneous diseases that undergo a variety of clinical courses and possess diverse therapeutic responses. Owing to the close association between its molecular subtypes and clinicopathological features, specific therapeutic strategies have recently been suggested. This review summarizes the current understanding of the molecular pathology of bladder cancer, including its molecular biomarkers/pathways and molecular subtypes that have been newly identified using high-throughput technologies. It also discusses advances in our understanding of personalized treatments for specific molecular subtypes.

Keywords: APOBEC; FGFR3; GATA3; PD-L1; The Cancer Genome Atlas (TCGA); immune checkpoint inhibitor; molecular pathological epidemiology; precision medicine; uroplakin; urothelial carcinoma.

Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Morphology of non-invasive bladder cancer (hematoxylin and eosin staining). (A) Non-invasive papillary tumor (pTa); (B) Carcinoma in situ (CIS; pTis). Scale bar = 100 µm.
Figure 2
Figure 2
Potential pathways of the tumorigenesis and tumor progression of bladder cancer [2,6,25]. Bladder cancer develops either via divergent pathways comprising either the FGFR3/RAS pathway (green) or the TP53/RB1 pathway (red). Chromosome nine deletion occurs in the early phase of tumorigenesis. FGFR3/HRAS mutation frequently occurs during the development of hyperplasia. In case of low-grade Ta carcinoma with recurrent PIK3CA/STAG2 mutation, hyperplasia develops into high-grade Ta carcinoma, which may progress to become T1 carcinoma after CDKN2A inactivation or TP53/RB1 inactivation. TP53 mutation frequently occurs during the development of dysplasia. Dysplasia may develop into CIS (Tis) after RB1, followed by T1 carcinoma. T1 carcinoma progresses to become MIBC (T2) after various genomic alterations. Chr, chromosome; CIS, carcinoma in situ; MIBC, muscle-invasive bladder cancer; mut, mutation.
Figure 3
Figure 3
(A) Basal type of bladder cancer (hematoxylin and eosin staining); (B) CK5/6 immunostaining (cytoplasmic; positive); (C) CD44 immunostaining (membranous; positive); (D) TP63 immunostaining (nuclear; positive); (E) EGFR immunostaining (membranous; positive). Scale bar = 100 µm.
Figure 4
Figure 4
(A) Luminal type of bladder cancer (hematoxylin and eosin staining); (B) KRT20 immunostaining (cytoplasmic; positive); (C) GATA3 immunostaining (nuclear; positive); (D) Uroplakin II immunostaining (cytoplasmic and membranous; positive); (E) ERBB2 immunostaining (membranous; positive). Scale bar = 100 µm.
Figure 5
Figure 5
The mRNA-based subtypes of muscle-invasive bladder cancer (MIBC) by The Cancer Genome Atlas consortium [13]. MIBC can be divided into five subtypes [luminal-papillary (35%), luminal-infiltrated (19%), luminal (6%), basal-squamous (35%) and neuronal (5%)].
Figure 6
Figure 6
Categorization of muscle-invasive bladder cancer into five different subtypes based on mRNA expression by The Cancer Genome Atlas consortium [13]. Molecular and clinicopathological characteristics and suggested treatments for the five subtypes are summarized. CIS, carcinoma in situ; EMT, epithelial-mesenchymal transition; NAC, neoadjuvant chemotherapy; SHH, sonic hedgehog.

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