Plasmacytoid Variant Bladder Cancers Harbor CDH1 Mutations

Bladder cancers have a large range of variant morphologies, and tumors with wholly variant histologies exhibit worse survival rates. Variant histology bladder cancers were not included in The Cancer Genome Atlas (TCGA), and, thus, the molecular events underlying these tumors remain poorly understood. Al-Ahmadie, Iyer, Lee, and colleagues used whole-exome and targeted sequencing to characterize plasmacytoid bladder cancer, an aggressive histologic variant cancer. Whole-exome sequencing of six plasmacytoid variant bladder tumors revealed truncating somatic mutations in cadherin 1 (CDH1), which encodes E-cadherin, in all of the tumors, whereas there were no CDH1-truncating mutations in the 127 bladder cancers in TCGA. The frequency of CDH1 mutations in plasmacytoid variant bladder cancer was further validated by targeted sequencing in an additional 19 tumors, with 74% containing CDH1 mutations. Aside from CDH1 mutations, the genomic profile of plasmacytoid variant tumors was similar to other bladder cancers, with mutations commonly occurring in TP53, RB1, ARID1A, ERBB2, and PIK3CA. The morphology of plasmacytoid variant tumors was similar to lobular breast carcinoma and diffuse gastric carcinoma, both of which also have frequent CDH1 mutations. Patients with plasmacytoid variant cancer had a poorer survival rate, increased incidence of recurrence, and an increased incidence of peritoneal spread compared to patients with other types of bladder cancer. To determine if loss of E-cadherin contributed to the aggressive phenotype, CDH1 was deleted by CRISPR/Cas9 in two urothelial carcinoma cell lines. CDH1 loss resulted in increased migration, suggesting that loss of E-cadherin may result in the increased invasiveness of plasmacytoid variant tumors. These findings indicate that plasmacytoid variant bladder cancers are characterized by CDH1 mutations that lead to the loss of E-cadherin and may be responsible for the aggressive phenotype of plasmacytoid variant tumors.

Al-Ahmadie HA, Iyer G, Lee BH, Scott SN, Mehra R, Bagrodia A, et al. Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. Nat Genet 2016 Feb 22 [Epub ahead of print].

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