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.
Highlights
With an estimated population incidence of about 1 in 370, Lynch syndrome represents the most common, autosomal dominantly inherited cancer predisposition worldwide [1], caused by germline mutations in DNA mismatch-repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2)
The initial investigation of a primary extra-osseous Ewing sarcoma from a MSH6 mutation carrier (c.3696dupT) previously affected by colon cancer revealed that the tumor displayed the typical hallmarks of Lynch syndrome, i.e., microsatellite instability (MSI) at mononucleotide markers and specific loss of MSH6 expression (Supplementary Fig. S1), but none of the molecular features commonly associated with Ewing sarcoma, i.e., chromosomal translocations involving the Ewing sarcoma breakpoint region 1 (EWSR1) gene locus on 22q12 (Supplementary Fig. S2)
Reasoning that the EWSR1 gene is likely involved in the development of this Ewing sarcoma tumor and in view of the tumor's MSIhigh phenotype, we focused on a mononucleotide tract in the 30 untranslated region (30-UTR) of the EWSR1 gene consisting of 16 thymines (EWS16T; c.Ã318_Ã333), which we thought would be a likely MSI target
Summary
With an estimated population incidence of about 1 in 370, Lynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer) represents the most common, autosomal dominantly inherited cancer predisposition worldwide [1], caused by germline mutations in DNA mismatch-repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). Mutation carriers are at an increased risk to develop colorectal cancer as well as a distinct spectrum of extracolonic cancers (predominantly of the endometrium, ovaries, and stomach) at a young age [2]. Biallelic inactivation of the MMR system leads to genome-wide accumulation of DNA replication errors at Authors' Affiliations: 1Biozentrum, University of Basel; 2Research Group Human Genetics, Dept of Biomedicine, University of Basel, and Division of Medical Genetics, University Hospital Basel; 3Institute for Surgical Research and Hospital Management and Department of Biomedicine, University of Basel; 4Institute of Pathology, University Hospital of Basel, Basel; 5Pathologie Laenggasse Bern, Bern; 6Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland; 7Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; and 8Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
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