Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer

Eur Urol. 2013 Feb;63(2):379-85. doi: 10.1016/j.eururo.2012.07.047. Epub 2012 Aug 2.


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.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinoma, Transitional Cell / epidemiology
  • Carcinoma, Transitional Cell / genetics*
  • Cohort Studies
  • DNA Mismatch Repair / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Kidney Neoplasms / epidemiology
  • Kidney Neoplasms / genetics*
  • Kidney Pelvis
  • Lynch Syndrome II / genetics*
  • Male
  • Microsatellite Instability
  • Middle Aged
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / genetics*
  • Nuclear Proteins / genetics*
  • Ontario / epidemiology
  • Registries
  • Risk Factors
  • Ureteral Neoplasms / epidemiology
  • Ureteral Neoplasms / genetics*
  • Urinary Bladder Neoplasms / epidemiology
  • Urinary Bladder Neoplasms / genetics*


  • Adaptor Proteins, Signal Transducing
  • MLH1 protein, human
  • Nuclear Proteins
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein