Spectrum of Phosphatidylinositol 3-Kinase Pathway Gene Alterations in Bladder Cancer

Abstract

Purpose: 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. Experimental Design: 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. (Clin Cancer Res 2009;15(19):6008-17)

PI3K signaling pathway is activated by PIK3CA mRNA overexpression and copy gain in prostate tumors, but PIK3CA, BRAF, KRAS and AKT1 mutations are infrequent events

“…Data from the literature reveal that independent bladder tumors harbor B13-25% of PIK3CA mutations. 25,26 We found a lower percentage of mutations of this gene (5%) in the bladder tumors from patients with prostate cancer. This difference could be related to the fact that bladder tumors in patients with and without prostate cancer could progress through different pathways, but it could also be explained by differences in the bladder tumors included in our study.…”

“…Previous papers on PIK3CA alterations in bladder cancer have reported from 13 to 25% of mutations in this gene, but with a higher prevalence in superficial than in deeply infiltrating bladder tumors. 25,26 In our study, most of the bladder samples were high-grade and high-stage tumors (Table 1). For this reason, we also investigated PIK3CA mutations in previous superficial bladder tumors in six patients from G2, also with negative results.…”

“…Most of the bladder tumors from G2 were muscle invasive, whereas PIK3CA mutations are more frequent in superficial tumors. 25,26 To investigate whether the differences in the prevalence of PIK3CA mutations were because of the invasive nature of the G2 bladder tumors, we selected six of these cases in which a previous, superficial, lowgrade bladder tumor was available, and we did not find PIK3CA mutations in any of them. Interestingly, the only bladder tumor with mutated PIK3CA in our study was deeply invasive and high grade (T3G3).…”

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

“…9,43-45 As a result, it is not surprising that PTEN loss is associated with aggressive tumor growth, metastases, and worsened patient outcomes. 46,47 In invasive UCC, PTEN is mutated or shows loss of heterozygosity (LOH) in up to 30% of cases, 9,48,49 whereas this number falls to 6.6% in superficial tumors (pTa/pT1). 42 One group actually reported reduced PTEN protein expression in 94% of advanced stage bladder cancer specimens, whereas only 42% of superficial tumors and 8% of carcinoma in situ (CIS) specimens had reduced PTEN expression.…”

The Molecular, the Bad, and the Ugly: Preventing Bladder Cancer via mTOR Inhibition

“…The second progression track involves the inactivation of major tumor suppressors [p53, Rb, and phosphatase and tensin homologue (PTEN); refs. 1,4,5], and it produces tumors that are highly invasive and metastatic. Although ∼50% of these muscle-invasive tumors respond well to cisplatin-based therapies (6,7), the other half is highly refractory to all current regimens and leads to rapid mortality.…”