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Frequent Microsatellite Instability in Sporadic Tumors of the Upper Urinary Tract¹

Institute of Pathology, University of Regensburg, 93042 Regensburg, Germany [A. H., L. Z., H. B., W. D., R. S., R. K., F. H.]; Genetics and Molecular Biology Program, Kimmel Cancer Center, Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [T. B-E., R. F.]; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota [J. C. C.]; Department of Urology, University of Jena, Jena, Germany [K. J.]; Department of Urology, St. Josefs Hospital, Regensburg, Germany [W. W.]; and Institute of Pathology, Kassel, Germany [J. R.]

Urothelial carcinoma of the renal pelvis and ureter may develop sporadically or as a manifestation of hereditary nonpolyposis colorectal cancer. The majority of hereditary nonpolyposis colorectal cancer is caused by mutation of the human DNA mismatch repair (MMR) genes and is detected by associated microsatellite instability (MSI). Seventy-three unselected urothelial carcinomas of the ureter and/or renal pelvis were screened for MSI using the National Cancer Institute-designated reference panel (plus BAT40). Instability of at least two microsatellite markers (MSI-high) was detected in 15 samples (21%). Immunohistochemical staining of the MMR proteins (hMSH2, hMLH1, or hMSH6) was absent in 13 of 15 (87%) MSI tumors, and alteration of coding sequence microsatellites (TGFßRII, Bax, hMSH3, and hMSH6) was found at frequencies of 7–33% in these samples. Tumors with MSI had significantly different clinical and histopathological features including higher prevalence in female patients, low tumor stage and grade, and a papillary and frequently inverted growth pattern. Our results suggest a molecular pathway of tumorigenesis that is similar to MMR-deficient colorectal cancers and consistent with the notion that the site distributions of hereditary or sporadic MSI-high tumors may reflect tissue-specific susceptibility to lesions processed by the MMR machinery.

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