ABSTRACT
Urothelial carcinoma of the renal pelvis is a deadly disease with an unclear tumorigenic mechanism. We conducted gene expression profiling on a set of human tumors of this type and identified a phosphatidylinositol 3-kinase (PI3K)/AKT activation expression signature in 76.9% (n = 13) of our samples. Sequence analysis found both activating mutations of PIK3CA (13.6%, n = 22) and loss of heterozygosity at the PTEN locus (25%, n = 8). In contrast, none of the other subtypes of kidney neoplasms (e.g., clear-cell renal cell carcinoma) harbored PIK3CA mutations (n = 87; P < 0.001). Immunohistochemical analysis of urothelial carcinoma samples found loss of PTEN protein expression (36.4%, n = 11) and elevation of phosphorylated mammalian target of rapamycin (mTOR; 63.6%, n = 11). To confirm the role of the PI3K/AKT pathway in urothelial carcinoma, we generated mice containing biallelic inactivation of Pten in the urogenital epithelia. These mice developed typical renal pelvic urothelial carcinomas, with an incidence of 57.1% in mice older than 1 year. Laser capture microdissection followed by PCR confirmed the deletion of Pten exons 4 and 5 in the animal tumor cells. Immunohistochemical analyses showed increased phospho-mTOR and phospho-S6K levels in the animal tumors. Renal lymph node metastases were found in 15.8% of the animals with urothelial carcinoma. In conclusion, we identified and confirmed an important role for the PI3K/AKT pathway in the development of urothelial carcinoma and suggested that inhibitors of this pathway (e.g., mTOR inhibitor) may serve as effective therapeutic agents.
Subject(s)
Kidney Neoplasms/pathology , Kidney Pelvis/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Papillary/genetics , Carcinoma, Papillary/metabolism , Carcinoma, Papillary/pathology , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Female , Gene Expression Profiling , Humans , Immunoenzyme Techniques , Integrases/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Kidney Pelvis/metabolism , Lasers , Loss of Heterozygosity , Male , Mice , Mice, Transgenic , Microdissection , Oligonucleotide Array Sequence Analysis , PTEN Phosphohydrolase/physiology , Phosphatidylinositol 3-Kinases/genetics , Protein Kinases/genetics , Protein Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , TOR Serine-Threonine Kinases , Urinary Bladder Neoplasms/geneticsABSTRACT
We report and characterize the copy number alterations (CNAs) in 35 clear cell and 12 papillary renal cell carcinomas (RCC) using Affymetrix 100K SNP arrays. Novel gain and loss regions are identified in both subtypes. In addition, statistically significant CNA are detected and associated with the pathological features: VHL mutation status, tumor grades, and sarcomatoid component in clear cell RCC and in types 1 and 2 of papillary RCC. Florescence in situ hybridization confirmed the copy number gain in the transforming growth factor, beta-induced gene (TGFBI), which is a possible oncogene for clear cell RCC.
