Abstract
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 (TGFbetaRII, 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adult
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Aged
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Aged, 80 and over
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Base Pair Mismatch
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Carrier Proteins
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DNA Repair / genetics
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Female
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Frameshift Mutation
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Humans
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Kidney Neoplasms / genetics*
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Kidney Pelvis / pathology
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Male
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Microsatellite Repeats / genetics*
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Middle Aged
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MutL Protein Homolog 1
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MutS Homolog 2 Protein
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Nuclear Proteins
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2*
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Receptor, IGF Type 2 / biosynthesis
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Receptor, IGF Type 2 / genetics
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / biosynthesis
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Receptors, Transforming Growth Factor beta / genetics
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Ureteral Neoplasms / genetics*
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Ureteral Neoplasms / metabolism
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Ureteral Neoplasms / pathology
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bcl-2-Associated X Protein
Substances
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Adaptor Proteins, Signal Transducing
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BAX protein, human
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Carrier Proteins
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DNA-Binding Proteins
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G-T mismatch-binding protein
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MLH1 protein, human
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Neoplasm Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptor, IGF Type 2
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Receptors, Transforming Growth Factor beta
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bcl-2-Associated X Protein
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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MSH2 protein, human
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MutL Protein Homolog 1
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MutS Homolog 2 Protein