Epigenetics Bladder Cancer

Published OnlineFirst March 3, 2016; DOI: 10.1158/2159-8290.CD-RW2016-040

RESEARCH WATCH

Bladder Cancer

Major finding: CDH1 mutations are Approach: Plasmacytoid variant tumors Impact: Plasmacytoid variant tumors specific to, and occur in the majority of, were molecularly characterized using are distinguishable from nonvariant plasmacytoid variant bladder cancers. whole-exome and targeted sequencing. bladder cancers by CDH1 mutations.

PLASMACYTOID VARIANT BLADDER CANCERS HARBOR CDH1 MUTATIONS Bladder cancers have a large range of variant mor- was similar to lobular breast carcinoma and diffuse phologies, and tumors with wholly variant histolo- gastric carcinoma, both of which also have frequent gies exhibit worse survival rates. Variant histology CDH1 mutations. Patients with plasmacytoid vari- bladder cancers were not included in The Cancer ant cancer had a poorer survival rate, increased inci- Genome Atlas (TCGA), and, thus, the molecular dence of recurrence, and an increased incidence of events underlying these tumors remain poorly peritoneal spread compared to patients with other understood. Al-Ahmadie, Iyer, Lee, and colleagues types of bladder cancer. To determine if loss of used whole-exome and targeted sequencing to char- E-cadherin contributed to the aggressive phenotype, acterize plasmacytoid bladder cancer, an aggressive histologic CDH1 was deleted by CRISPR/Cas9 in two urothelial carci- variant cancer. Whole-exome sequencing of six plasmacytoid noma cell lines. CDH1 loss resulted in increased migration, variant bladder tumors revealed truncating somatic muta- suggesting that loss of E-cadherin may result in the increased tions in cadherin 1 (CDH1), which encodes E-cadherin, in all invasiveness of plasmacytoid variant tumors. These ﬁ ndings of the tumors, whereas there were no CDH1-truncating muta- indicate that plasmacytoid variant bladder cancers are charac- tions in the 127 bladder cancers in TCGA. The frequency of terized by CDH1 mutations that lead to the loss of E-cadherin CDH1 mutations in plasmacytoid variant bladder cancer was and may be responsible for the aggressive phenotype of plas- further validated by targeted sequencing in an additional 19 macytoid variant tumors. ■ tumors, with 74% containing CDH1 mutations. Aside from CDH1 mutations, the genomic proﬁ le of plasmacytoid vari- Al-Ahmadie HA, Iyer G, Lee BH, Scott SN, Mehra R, Bagrodia A, ant tumors was similar to other bladder cancers, with muta- et al. Frequent somatic CDH1 loss-of-function mutations in plasma- tions commonly occurring in TP53, RB1, ARID1A, ERBB2, and cytoid variant bladder cancer. Nat Genet 2016 Feb 22 [Epub ahead PIK3CA. The morphology of plasmacytoid variant tumors of print].

Epigenetics

Major finding: Microdeletions in non- Mechanism: Disruption of insulated loop Impact: Insulated neighborhood dis- coding boundary elements can acti- boundaries allows regulatory elements ruption can activate oncogenes with- vate proto-oncogenes in T-ALL. outside the loop to activate oncogenes. out alterations in the target locus.

DISRUPTING INSULATED CHROMOSOME NEIGHBORHOODS CAN ACTIVATE ONCOGENES Proto-oncogenes can be activated by multiple mechanisms, ary site suggest that boundary disruption may allow control by including alterations that bring enhancers into proximity to regulatory elements outside the insulated neighborhood. Con- regulate its expression. Enhancers form DNA loops to inter- sistent with these fi ndings, deletion of the TAL1 neighborhood act with target genes, and are regulated within larger CTCF- boundary with CRISPR/Cas9 is suffi cient to activate TAL1, cohesin–mediated loops, termed insulated neighborhoods. and similar results were observed with deletion of the LMO2 Hnisz, Weintraub, and colleagues hypothesized that disruption boundary. Further, analysis of mutations in cancer genomes of the insulated neighborhoods might lead to aberrant activa- from the ICGC database indicates an enrichment of muta- tion of proto-oncogenes by enhancer elements typically found tions at boundary CTCF sites, but not non-boundary CTCF outside of the neighborhood. The Insulated neighborhoods sites, suggesting that disruption of insulated neighborhoods were mapped in a T-cell acute lymphoblastic leukemia (T-ALL) may activate oncogenes in other tumor types. Together, these cell line using chromatin interaction analysis by paired-end tag fi ndings highlight a mechanism by which proto-oncogenes can sequencing (ChIA-PET) to identify cohesin sites, as cohesin has be activated through disruption of the insulated chromosome been shown to identify insulated neighborhoods. The major- neighborhood boundary, leading to oncogene regulation by ity of genes known to be involved in promoting T-ALL, both enhancers outside of the neighborhood, and this mechanism active oncogenes and silent proto-oncogenes, were located may occur across tumor types. ■ within the identifi ed insulated neighborhoods in the T-ALL cells. Several common T-ALL deletions were found to affect Hnisz D, Weintraub AS, Day DS, Valton A-L, Bak RO, Li CH, insulated neighborhood boundaries, including deletions in et al. Activation of proto-oncogenes by disruption of chromosome TAL1 and LMO2, and deletions overlapping the CTCF bound- neighborhoods. Science 2016 Mar 3 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.

APRIL 2016CANCER DISCOVERY | 343

Plasmacytoid Variant Bladder Cancers Harbor CDH1 Mutations

Cancer Discov 2016;6:343. Published OnlineFirst March 3, 2016.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2016-040

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