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3'-UTR Poly(T/U) tract deletions and altered expression of EWSR1 are a hallmark of mismatch repair-deficient cancers


Kishore, Shivendra; Piscuoglio, Salvatore; Kovac, Michal B; Gylling, Annette; Wenzel, Friedel; Trapani, Francesca; Altermatt, Hans Joerg; Mele, Valentina; Marra, Giancarlo; Peltomäki, Päivi; Terracciano, Luigi; Zavolan, Mihaela; Heinimann, Karl (2014). 3'-UTR Poly(T/U) tract deletions and altered expression of EWSR1 are a hallmark of mismatch repair-deficient cancers. Cancer Research, 74(1):224-234.

Abstract

The genome-wide accumulation of DNA replication errors known as microsatellite instability (MSI) is the hallmark lesion of DNA mismatch repair (MMR)-deficient cancers. Although testing for MSI is widely used to guide clinical management, the contribution of MSI at distinct genic loci to the phenotype remains largely unexplored. Here, we report that a mononucleotide (T/U)16 tract located in the 3' untranslated region (3'-UTR) of the Ewing sarcoma breakpoint region 1 (EWSR1) gene is a novel MSI target locus that shows perfect sensitivity and specificity in detecting mismatch repair-deficient cancers in two independent populations. We further found a striking relocalization of the EWSR1 protein from nucleus to cytoplasm in MMR-deficient cancers and that the nonprotein-coding MSI target locus itself has a modulatory effect on EWSR1 gene expression through alternative 3' end processing of the EWSR1 gene. Our results point to a MSI target gene-specific effect in MMR-deficient cancers. Cancer Res; 74(1); 224-34. ©2013 AACR.

Abstract

The genome-wide accumulation of DNA replication errors known as microsatellite instability (MSI) is the hallmark lesion of DNA mismatch repair (MMR)-deficient cancers. Although testing for MSI is widely used to guide clinical management, the contribution of MSI at distinct genic loci to the phenotype remains largely unexplored. Here, we report that a mononucleotide (T/U)16 tract located in the 3' untranslated region (3'-UTR) of the Ewing sarcoma breakpoint region 1 (EWSR1) gene is a novel MSI target locus that shows perfect sensitivity and specificity in detecting mismatch repair-deficient cancers in two independent populations. We further found a striking relocalization of the EWSR1 protein from nucleus to cytoplasm in MMR-deficient cancers and that the nonprotein-coding MSI target locus itself has a modulatory effect on EWSR1 gene expression through alternative 3' end processing of the EWSR1 gene. Our results point to a MSI target gene-specific effect in MMR-deficient cancers. Cancer Res; 74(1); 224-34. ©2013 AACR.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2014
Deposited On:04 Mar 2014 09:58
Last Modified:21 Nov 2017 19:55
Publisher:American Association for Cancer Research
ISSN:0008-5472
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/0008-5472.CAN-13-2100
PubMed ID:24158095

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