Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer.
OBJECTIVE
The phosphatidylinositol 3-kinase (PI3K) pathway can be activated by alterations affecting several pathway components. For rational application of targeted therapies, detailed understanding of tumor biology and approaches to predict efficacy in individual tumors are required. Our aim was to assess the frequency and distribution of pathway alterations in bladder cancer.


METHODS
We examined the pathway components (PIK3CA, PTEN, TSC1, RHEB, and LKB1) and putative upstream regulators (FGFR3 and RAS genes) for mutation, allelic loss, copy number alteration, and expression in bladder tumors and cell lines.


RESULTS
No mutations were found in RHEB and only a single mutation in LKB1. PIK3CA mutations were detected in 25% of tumors and 26% of cell lines with a significant excess of helical domain mutations (E542K and E545K). There was over-representation but not amplification of the gene. Loss of heterozygosity of the PTEN region and homozygous deletion were found in 12% and 1.4% of tumors, and reduced expression in 49%. Forty-six percent of cell lines showed alterations that implicated PTEN. Sixteen percent of tumors and 11% of cell lines showed TSC1 mutation, and 9q loss of heterozygosity was common (57%). Pathway alterations were independently distributed, suggesting that the mutation of two pathway members may have additive or synergistic effects through noncanonical functions.


CONCLUSIONS
PI3K pathway alterations are common in bladder cancer. The lack of redundancy of alterations suggests that single-agent PI3K-targeted therapy may not be successful in these cancers. This study provides a well-characterized series of cell lines for use in preclinical studies of targeted agents.
Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, United Kingdom.
Fiona M
FM
Platt
Carolyn D
CD
Hurst
Claire F
CF
Taylor
Walter M
WM
Gregory
Patricia
P
Harnden
Margaret A
MA
Knowles
D000091162:AMP-Activated Protein Kinase Kinases; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000076205:Ras Homolog Enriched in Brain Protein; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism; D019459:Urothelium / Q000473:pathology
D000091162:AMP-Activated Protein Kinase Kinases; D020559:Monomeric GTP-Binding Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000076205:Ras Homolog Enriched in Brain Protein; D051498:Receptor, Fibroblast Growth Factor, Type 3; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C503859:PI3KCA protein, human; C490211:RHEB protein, human; C000624650:TSC1 protein, human; C496365:FGFR3 protein, human; C109790:STK11 protein, human; C494929:PTEN protein, human