Elsevier

European Urology

Volume 63, Issue 2, February 2013, Pages 379-385
European Urology

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

https://doi.org/10.1016/j.eururo.2012.07.047Get rights and content

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.

Introduction

Previous studies have suggested a hereditary factor in bladder cancer (BCa), urothelial carcinoma (UC) type, with first-degree relatives having an approximately 2 times increased risk [1], [2]. It is uncertain whether this finding represents evidence of a genetic and/or shared environmental basis for familial aggregation. Recently, several gene variants have been shown to confer susceptibility to BCa [3], [4].

Epidemiological studies have demonstrated inheritance for upper tract UC (UTUC). Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome caused by germline mutations in the DNA mismatch repair (MMR) genes mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2) [5]. Defective MMR function leads to genetic instability, detected as novel alterations in microsatellite regions of DNA, which are short, repetitive sequences (one to five nucleotides) located throughout the genome [6]. Microsatellite instability (MSI) is a hallmark feature seen in approximately 85% of LS-associated tumors in mutation carriers [7]. Immunohistochemistry (IHC) is another tool used to recognize LS, with 95% sensitivity for detecting the absence of expression of MMR proteins. Individuals with familial clustering of colorectal and other LS-associated tumors are generally referred to predictive genetic testing programs for screening of germline MMR gene mutations.

LS patients are at an increased risk for other extracolonic cancers such as endometrial cancer (27–71%), gastric cancer (2–13%), ovarian cancer (3–13%), and of interest to urologists, UTUC [8]. Studies about the risk of BCa in LS have been limited [9]. The goal of this study was to further investigate the risk of bladder UC in LS patients, in addition to the already reported increased risk for UTUC.

Section snippets

Study subjects

The Familial Gastrointestinal Cancer Registry (FGICR) (Mount Sinai Hospital, Toronto, Ontario, Canada) comprises families in Ontario diagnosed with rare forms of inherited gastrointestinal cancers who consent to be included. The registry was analyzed to isolate a subset of patients with confirmed MMR mutations in MLH1, MSH2, MSH6, or PMS2 genes from 1980 to 2007. The Research Ethics Board approved all study protocols. All confirmed mutation carriers were reviewed for a history of cancer of the

Patient population

A total of 321 patients were identified with confirmed MMR gene mutations. Germline MSH2 and MLH1 mutations were the most common, whereas MSH6 and PMS2 mutations were rare (Table 1).

Eleven of 177 patients with MSH2 mutations (6.21%) had confirmed BCa (Table 2), which was significantly above the average rate expected in the general population compared with gender- and age-specific lifetime risks obtained from Canadian Cancer Statistics 2011 (3.6% for men and 1.2% for women, p < 0.001). The average

Discussion

The increased incidence of UC in LS was first reported by Vasen et al. in 1990 [14], with eight patients from four families being diagnosed. Subsequent studies investigating the tumor spectrum of families meeting the Amsterdam criteria or Bethesda criteria have supported this finding, with an increased risk of 4–17 times and 8–22 times seen for renal pelvis and ureter UC, respectively [15], [16], [17]. MSH2 mutation carriers have a significantly higher risk of UC compared with MLH1 carriers,

Conclusions

Our study suggests that family members of LS patients with MSH2 mutations are at an increased risk not only for UTUC but also for BCa. First-degree relatives from MSH2 mutation families, as well as patients with known MSH2 mutations, could be offered screening for UCs.

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