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

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.

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Figures and tables from this article:

Fig. 1. Tumor sections at ×200 magnification: (A) abnormal MSH2 expression—nuclear expression is lost in the tumor, with normal nuclear staining in the adjacent tissue; (B) normal MLH1 expression—normal strong nuclear expression in the tumor and normal tissue.

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Table 1. Distribution of patients with mismatch repair mutations

M:F = male-to-female; MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); MSH6 = mutS homolog 6 (E. coli); PMS2 = PSM2 postmeiotic segregation increased 2 (S. cerevisiae).

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Table 2. Total incidence of urothelial cancers due to MLH1 and MSH2

MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); NS = not significant.

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Table 3. Urothelial cancers in patients with confirmed MSH2 mutations and comparison with matched sporadic bladder cancer patients

− = absent expression; +  = normal expression; CR = colorectal; Dx = diagnosis; EM = endometrial; F = female; GA = gastric; HG = high grade; IHC = immunohistochemistry; LG = low grade; LS = Lynch syndrome; M = male; MSH2 = mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli); MSI = microsatellite instability; MSI-H = high microsatellite instability; MSS = microsatellite stable; OR = occupational risk; OV = ovarian; RP = renal pelvis; U = ureter.Patients H1 and H2 are related.

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Table 4. Urothelial cancers in patients with confirmed MLH1 mutations

− = absent expression; +  = normal expression; CR = colorectal; HG = high grade; IHC = immunohistochemistry; LG = low grade; LS = Lynch syndrome; M = male; MLH1 = mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli); MSI = microsatellite instability; MSI-H = high microsatellite instability; OR = occupational risk; RP = renal pelvis.