1244 INVESTIGATING BLADDER CANCER RISK IN HEREDITARY NON-POLYPOSIS COLORECTAL CANCER PATIENTS WITH MISMATCH REPAIR GENE MUTATIONS

You have accessJournal of UrologyBladder Cancer: Detection and Screening1 Apr 20111244 INVESTIGATING BLADDER CANCER RISK IN HEREDITARY NON-POLYPOSIS COLORECTAL CANCER PATIENTS WITH MISMATCH REPAIR GENE MUTATIONS Sean C. Skeldon, Melyssa Aronson, Kara Semotiuk, Aaron Pollett, Bas W.G. van Rhijn, Peter J. Bostrom, Steven Gallinger, Zane Cohen, Neil E. Fleshner, Michael A. Jewett, Sally Hanna, Cynthia Kuk, Theodorus H. van der Kwast, Andrew Evans, Bharati Bapat, and Alexandre R. Zlotta Sean C. SkeldonSean C. Skeldon Toronto, Canada More articles by this author , Melyssa AronsonMelyssa Aronson Toronto, Canada More articles by this author , Kara SemotiukKara Semotiuk Toronto, Canada More articles by this author , Aaron PollettAaron Pollett Toronto, Canada More articles by this author , Bas W.G. van RhijnBas W.G. van Rhijn Toronto, Canada More articles by this author , Peter J. BostromPeter J. Bostrom Toronto, Canada More articles by this author , Steven GallingerSteven Gallinger Toronto, Canada More articles by this author , Zane CohenZane Cohen Toronto, Canada More articles by this author , Neil E. FleshnerNeil E. Fleshner Toronto, Canada More articles by this author , Michael A. JewettMichael A. Jewett Toronto, Canada More articles by this author , Sally HannaSally Hanna Toronto, Canada More articles by this author , Cynthia KukCynthia Kuk Toronto, Canada More articles by this author , Theodorus H. van der KwastTheodorus H. van der Kwast Toronto, Canada More articles by this author , Andrew EvansAndrew Evans Toronto, Canada More articles by this author , Bharati BapatBharati Bapat Toronto, Canada More articles by this author , and Alexandre R. ZlottaAlexandre R. Zlotta Toronto, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.915AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Hereditary non-polyposis colorectal cancer (HNPCC) is caused by mutations in mismatch repair (MMR) genes. Increased risk for urothelial cell carcinoma (UCC) of the ureter has been described, specifically in those with MSH2 gene mutation. We have previously shown a link between MSH2 mutation and an increased risk of bladder cancer (BC). Here, we aim to confirm previous reports and identify a link between MSH2, upper urinary tract (UUT)-UCC and BC at the tissue level. METHODS BC and UUT-UCC risk was analyzed in MMR gene mutation carriers within the Familial Gastrointestinal Cancer Registry (FGICR) in Toronto, Canada. Data between 1970 to 2007 was obtained from the FGICR of 321 persons with known mutations (MLH1, MSH2, MSH6, PMS2). 177 patients had germline MSH2 mutations and 129 patients carried MLH1 mutations. Standardized incidence ratios in Canada were used to compare cancer risk in patients with confirmed germline MMR mutations to the general population. Microsatellite instability (MSI) analysis and immunohistochemistry (IHC) of the MMR proteins were performed and compared to gender, stage and grade matched sporadic bladder tumours to provide a histological correlation. RESULTS Among 177 MSH2 mutation patients, BC was found in 11 (6.21%) patients but only in 3 of 129 patients (2.32%) with MLH1 mutations. No patients with germline MSH6 or PMS2 mutations had a diagnosis of BC. Of the 11 patients with MSH2 mutations, there were 5 men and 6 women, which is in contrast to the expected male to female ratio for BC of 3:1 in Canada. This 6.21% incidence of BC among MSH2 carriers is significantly increased compared to the lifetime risk seen in the Canadian general population. 9 of 11 tumours (81.8%) were MSH2 deficient on IHC and 6 of these were MSI-H, 0% lacked expression of MLH1 while all matched sporadic cases displayed normal expression of MSH2 and MLH1. Among MSH2 carriers, UUT-UCC was found in 7 (3.95%) patients. All 7 tumours were found to be deficient in MSH2 expression and 5 of the 7 (71.4%) tumors were MSI-H. CONCLUSIONS HNPCC patients with germline MSH2 mutations are at an increased risk not only for UUT-UCC but also for BC. Family members of germline MSH2 mutation carriers should be screened for urinary UCC. In addition, sporadic UUT-UCC diagnosed in patients under 60 years old or with a family history of HNPCC-related cancers should be screened for HNPCC by IHC analysis of MMR proteins. Our study suggests that mutations of MMR genes may have an important contribution in the development of a subset of UCC. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e498 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sean C. Skeldon Toronto, Canada More articles by this author Melyssa Aronson Toronto, Canada More articles by this author Kara Semotiuk Toronto, Canada More articles by this author Aaron Pollett Toronto, Canada More articles by this author Bas W.G. van Rhijn Toronto, Canada More articles by this author Peter J. Bostrom Toronto, Canada More articles by this author Steven Gallinger Toronto, Canada More articles by this author Zane Cohen Toronto, Canada More articles by this author Neil E. Fleshner Toronto, Canada More articles by this author Michael A. Jewett Toronto, Canada More articles by this author Sally Hanna Toronto, Canada More articles by this author Cynthia Kuk Toronto, Canada More articles by this author Theodorus H. van der Kwast Toronto, Canada More articles by this author Andrew Evans Toronto, Canada More articles by this author Bharati Bapat Toronto, Canada More articles by this author Alexandre R. Zlotta Toronto, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...