Expression of the human mismatch repair gene hMSH2 - A potential marker for urothelial malignancy

BACKGROUND. The human mismatch repair (MMR) gene hMSH2 (human mutS homolog- 2) is a DNA repair gene that has been reported to be mutated in 40% of here ditary nonpolyposis colon cancer (HNPCC) kindreds and a small percentage of sporadic tumors. HNPCC is a cancer predisposition syndrome with an increas ed risk of carcinoma of the colon, endometrium, stomach, small intestine, o vary, ureter, and renal pelvis. Immunohistochemical analysis demonstrated i ncreased hMSH2 expression in sporadic colon carcinoma and in the replicativ e compartment of normal epithelium. A recent immunohistochemical analysis o f hMSH2 in bladder tumors correlated reduced hMSH2 expression with recurren ce and higher tumor grade. In the current study, we examined hMSH2 expressi on in urothelial malignancy using immunohistochemical analysis and develope d a molecular assay for the detection of hMSH2 expression in bladder washes . METHODS. Immunohistochemical analysis of 17 tumors from the genitourinary t ract and reverse transcription coupled with polymerase chain reaction (RT-P CR) of 40 bladder washes were used to investigate hMSH2 expression in nonin vasive and invasive urothelial malignancies. RESULTS. Increased expression of hMSH2 was detected in all tumors examined using immunohistochemical analysis independent of grade or stage. Reverse t ranscription-PCR of hMSH2 mRNA from bladder washes detected 17 of 21 patien ts with primary or recurrent urothelial neoplasms or tumors involving the u rothelial system. Four patients with urothelial malignancies without detect able hMSH2 expression from their bladder washes had high grade lesions. Ten of 13 patients without pathologic or cystoscopic evidence of bladder tumor s were negative for hMSH2 expression in bladder washes. Two patients with b ladder tumors and bladder washes that were positive for hMSH2 subsequently were found to be negative for hMSH2 after treatment of their tumors and at last follow-up had remained recurrence free for at least 1 year. CONCLUSIONS. The results of the current study suggest that hMSH2 expression is increased in low and high grade urothelial neoplasms, similar to the ex pression pattern in sporadic colon carcinoma. However, a fraction of high g rade lesions may not express hMSH2 as detected by RT-PCR from bladder washe s. The ability to detect hMSH2 expression in bladder washes may allow the u se of hMSH2 expression as a marker for urothelial malignancy. In addition, the ability to define hMSH2 deficient tumors using bladder washes may have prognostic significance in the treatment of patients with urothelial carcin oma. Cancer 2000;88:2333-41. (C) 2000 American Cancer Society.