doi: 10.1038/ng.3503.
Epub 2016 Feb 22.
Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer
Affiliations
- PMID: 26901067
- PMCID: PMC4827439
- DOI: 10.1038/ng.3503
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Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer
Nat Genet.
2016 Apr.
Abstract
Plasmacytoid bladder cancer is an aggressive histologic variant with a high risk of disease-specific mortality. Using whole-exome and targeted sequencing, we find that truncating somatic alterations in the CDH1 gene occur in 84% of plasmacytoid carcinomas and are specific to this histologic variant. Consistent with the aggressive clinical behavior of plasmacytoid carcinomas, which frequently recur locally, CRISPR/Cas9-mediated knockout of CDH1 in bladder cancer cells enhanced cell migration.
Conflict of interest statement
The authors declare no competing interests as defined by Nature Publishing Group, or other interests that might be perceived to influence the results and/or discussion reported in this paper.
Figures
a) Heatmap comparing the frequency and distribution of CDH1 alterations and select co-altered genes within 25 plasmacytoid-variant bladder cancers (including the 6 tumors analyzed by WES), a prospective cohort of 62 urothelial carcinomas (including 6 with plasmacytoid-variant histology), and 121 muscle-invasive urothelial carcinoma, NOS samples (urothelial TCGA). Star: Six CDH1 mutant plasmacytoid-variant tumors from the prospective clinical cohort. b) Comparison of frequencies of select genetic alterations between 31 plasmacytoid-variant bladder cancers, 127 urothelial TCGA samples, and a prospective institutional cohort of 56 urothelial carcinoma, NOS tumors. Asterisk: p < 0.05. c) Representative H&E images of plasmacytoid-variant bladder, lobular breast, and diffuse gastric carcinomas (top). Distribution of CDH1 alterations in all 3 tumor types are displayed (bottom). Stars: nonsense, frameshift, splice site mutations; triangles: point mutations; bars: indels. Cad_pro: Cadherin prodomain; Cadherin_C: Cadherin cytoplasmic domain.
a–b) Cancer-specific mortality and disease recurrence following radical cystectomy are shown in patients with plasmacytoid-variant or urothelial carcinoma, NOS tumors. c) Immunoblot of RT4 and MGHU4 bladder cancer cell lines subjected to CRISPR-mediated genetic deletion of CDH1. d–e)
In vitro scratch assay of MGHU4 cells with or without CDH1 deletion. Error bars represent median and interquartile range. f) Boyden chamber assay of RT4 and MGHU4 cells with or without CDH1 deletion. Asterisk: p < 0.05.