Articles

Bladder Cancer

Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer

By: Sean C. Skeldona, Kara Semotiukb, Melyssa Aronsonb, Spring Holterb, Steven Gallingerb, Aaron Pollettc, Cynthia Kuka d, Bas van Rhijna e, Peter Bostroma, Zane Cohenb, Neil E. Fleshnera, Michael A. Jewetta, Sally Hannaa d, Shahrokh F. Shariatf, Theodorus H. Van Der Kwastg h, Andrew Evansg, Jim Cattoi, Bharati Bapatb and Alexandre R. Zlottaa d lowast

European Urology, Volume 63 Issue 1, February 2013, Pages 379-385

Published online: 01 February 2013

Keywords: Bladder cancer, Lynch syndrome, MSH2, Microsatellite instability, Mismatch repair, Genetic

Abstract Full Text Full Text PDF (513 KB)

Abstract

Background

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse.

Objective

To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations.

Design, setting, and participants

Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2).

Outcome measurements and statistical analysis

Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors.

Results and limitations

Eleven of 177 patients with MSH2 mutations (6.21%, p<0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p>0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p<0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias.

Conclusions

LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.

Take Home Message

Our study demonstrates an increased risk for bladder cancer in patients with mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2) mutations. Mutation carriers should be offered screening for cancer of the entire urothelium, as they are at an increased risk for both bladder and upper tract cancers.

Keywords: Bladder cancer, Lynch syndrome, MSH2, Microsatellite instability, Mismatch repair, Genetic.

Footnotes

a Department of Surgical Oncology, Urology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada

b Familial Gastrointestinal Cancer Registry, Zane Cohen Center for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada

c Department of Pathology, Mount Sinai Hospital, Toronto, Ontario, Canada

d Department of Surgery, Urology, Mount Sinai Hospital, Toronto, Ontario, Canada

e Department of Urology, Erasmus MC, Rotterdam, The Netherlands

f Department of Urology and Division of Medical Oncology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA

g Department of Pathology, University Health Network, Toronto, Ontario, Canada

h Department of Pathology, Erasmus MC, Rotterdam, The Netherlands

i Academic Urology Unit and Institute for Cancer Studies, University of Sheffield, Sheffield, United Kingdom

lowast Corresponding author. Department of Surgery, Division of Urology, University of Toronto, Mount Sinai Hospital and University Health Network, 60 Murray St., 6th Floor, Box 19, Toronto, Ontario, M5T 3L9, Canada. Tel. +1 416 586 4800, ext. 3910; Fax: +1 416 586 4776.

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