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.

Ovarian Endometrioid Adenocarcinoma: Incidence and Clinical Significance of the Morphologic and Immunohistochemical Markers of Mismatch Repair Protein Defects and Tumor Microsatellite Instability

"Ovarian cancer, particularly endometrioid (cell type)adenocarcinoma, is also associated with Lynch syndrome.....Overall, 10% of tumors had abnormal MMR protein status, defined as complete immunohistochemical loss of expression of MLH1, MSH2, MSH6, and/or PMS2.....Concurrent uterine tumor was present in 5/7 patients whose ovarian tumor had abnormal MMR/MSI.......Although abnormal MMR/MSI did not carry prognostic value in this study, it did predict the involvement of the uterus by the tumor. Thus, in patients with ovarian endometrioid adenocarcinoma who undergo uterus-sparing surgery, abnormal MMR/MSI should prompt further diagnostic evaluation of the endometrium for tumor."

 

medical news: New Class of Cancer Drugs Could Work in Colon Cancers with Genetic Mutation (PARP inhibitors/MRE11 gene/Lynch Synrome))

15% of colorectal cancers have mutation that responds to PARP inhibitors

Newswise — ANN ARBOR, Mich. — A class of drugs that shows promise in breast and ovarian cancers with BRCA gene mutations could potentially benefit colorectal cancer patients with a different genetic mutation, a new study from the University of Michigan Comprehensive Cancer Center finds.

Working in cell lines from colorectal cancer patients, researchers found that a new class of drugs called PARP inhibitors worked against tumors with mutations in the MRE11 gene.

full free access: World Jnl Gastroenterology-Approach to early-onset colorectal cancer: Clinicopathological, familial, molecular and immunohistochemical characteristics

 World Journal of Gastroenterology - link to article    

Keywords (article) : Early onset colorectal cancer, Microsatellite instability, Lynch syndrome, Microsatellite stable colorectal cancer

abstract/free full access: Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers -- Sjursen et al. -- Journal of Medical Genetics

Conclusion:
Amsterdam criteria and each of the Bethesda criteria were inadequate for identifying MSH6 mutation-carrying kindreds. MSH6 mutations may be more common than currently assumed, and the penetrance/expression of MSH6 mutations, as derived from families meeting current clinical criteria, may be misleading. To increase detection rate of MMR mutation carriers, all cancers in the Lynch syndrome tumour spectrum should be subjected to immunohistochemical analysis and/or analysis for microsatellite instability.