Multiple Genetic Alterations within the PI3K Pathway Are Responsible for AKT Activation in Patients with Ovarian Carcinoma

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is activated in multiple cancers including ovarian carcinoma (OC). However, the relative contribution of the single components within the PI3K pathway to AKT activation in OC is still unclear. We examined 98 tumor samples from Italian OC patients for alterations in the members of the PI3K pathway. We report that AKT is significantly hyperactive in OC compared to normal tissue (n = 93; p<0.0001) and that AKT activation is preferentially observed in the elderly (>58 years old; n = 93; p<0.05). The most frequent alteration is the overexpression of the p110α catalytic subunit of PI3K (63/93, ∼68%); less frequent alterations comprise the loss of PTEN (24/89, 27%) and the overexpression of AKT1 (18/96, 19%) or AKT2 (11/88,12.5%). Mutations in the PIK3CA or KRAS genes were detected at lower frequency (12% and 10%, respectively) whereas mutations in AKT1 or AKT2 genes were absent. Although many tumors presented a single lesion (28/93, of which 23 overexpressed PIK3CA, 1 overexpressed AKT and 4 had lost PTEN), many OC (35/93) presented multiple alterations within the PI3K pathway. Apparently, aberrant PI3K signalling was mediated by activation of the canonical downstream AKT-dependent mTOR/S6K1/4EBP1 pathway and by regulation of expression of oncogenic transcription factors that include HMGA1, JUN-B, FOS and MYC but not by AKT-independent activation of SGK3. FISH analysis indicated that gene amplification of PIK3CA, AKT1 and AKT2 (but not of PI3KR1) and the loss of PTEN are common and may account for changes in the expression of the corresponding proteins. In conclusion, our results indicate that p110α overexpression represents the most frequent alteration within the PI3K/AKT pathway in OC. However, p110α overexpression may not be sufficient to activate AKT signalling and drive ovarian tumorigenesis since many tumors overexpressing PI3K presented at least one additional alteration.

Detection of PIK3R1 (L449S) Mutation in a Patient with Ovarian Cancer: A Case Report

“…This alteration might be a key factor to enhance the effect of PIK3CA amplification in activating AKT/mTOR pathway and driving tumorigenesis. In most OC cases, PIK3CA (also called p110) and PIK3R1 (also called p85α) were overexpressed [12]. However, in the present case, a mutation in the inhibitory iSH2 domain of PIK3R1 was reported in coordination with PIK3CA amplification.…”

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

“…As the FOS transcription factor controls some of the same downstream targets of the PTEN-mTOR pathway (Koul et al 2007;De Marco et al 2013), it is possible that the genetic background of a boxer could make them more sensitive to a mutation in the PTEN-mTOR pathway in relevant cell types compared to the average dog. It has been shown that genetic background predisposes to specific cancers, even specific lymphoma subtypes.…”

AKT-independent PI3-K signaling in cancer &ndash; emerging role for SGK3

“…Finally, overexpression of SGK3 significantly correlates with poor overall survival of HCC patients ( P = 0.028) 20. However, in contrast to these studies demonstrating a role for SGK3 in AKT-independent oncogenic signaling, a recent report failed to demonstrate a role for SGK3 in mediating aberrant PI3-K activity in a panel of ovarian tumor samples exhibiting low AKT activation 89. Specifically, tumors presenting with low phosphorylated AKT but with high PIK3CA , SGK3 activation was detected in only 36% of ovarian tumors, and SGK3 phosphorylation did not correlate with phosphorylated PIK3CA overexpression or AKT activation.…”