Reply: Somatic mutations are present in all members of the AKT family in endometrial carcinoma

Reply: Somatic mutations are present in all members of the AKT family in endometrial carcinoma


Sir,
We appreciate the attention given by Drs Dutt, Salvesen, Greulich, Sellers, Beroukhim and Meyerson to our recent publication 'The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas' (Shoji et al, 2009). In this article, we report a 2% mutational frequency of AKT1 (E17K) among 101 endometrial carcinomas. We also described that these two AKT1 mutant tumours do not possess any mutations in PIK3CA, PTEN and K-Ras. Our report has proposed two issues to be clarified: (1) Are there any 'oncogenic' mutations in other AKT family members in endometrial carcinomas? (2) Are all the AKT family mutations mutually exclusive with other PI3 kinase-AKT-activating mutations?
Including the data in their earlier report, Dutt et al (2008) revealed mutations in AKT2 and AKT3, as well as in AKT1. As for AKT1 (E17K) mutations, their data and our data are compatible, showing that AKT1 mutations were detected in 2% of the endometrioid subtype in endometrial cancer. Compared with the accumulative data in AKT1 (E17K) mutations, mutations in AKT2 and AKT3 are not well characterised. Carpten et al (2007) and Kim et al (2008) reported no E17K mutations in AKT2 and AKT3 in breast, colorectal, gastric, hepatocellular, lung carcinomas and acute leukaemias. Davies et al (2008) first reported AKT3 (E17K) mutations in melanoma at 1.5% frequency. Parsons et al (2005) found two mutations of AKT2 (S302G and R371H) in 204 colorectal cancer samples, and Soung et al (2006) reported one missense mutation (A377V) and two possible splice-site mutations in intron 11 of AKT2 in gastric and lung adenocarcinoma. However, the physiological role of AKT2 mutations, including those (D399N, R368C and D32H) reported by Dutt et al (2008), has not been validated yet. In addition, the AKT3 (E438D) mutation has not been reported in any type of tumours. It is important to clarify whether these rare AKT2/3 mutations cause an oncogenic effect in cancer.
We previously reported that PIK3CA mutations frequently coexist with mutations in PTEN and/or KRAS, and suggested that the PIK3CA mutation might require another upstream input to fully activate the PI3K kinase -AKT pathway (Oda et al, 2005(Oda et al, , 2008. Their data of coexistent mutations in AKT1 (E17K) and KRAS (G13D) suggest that the KRAS mutation alone is insufficient for a full activation of the PI3 kinase -AKT pathway. Their data are not inconsistent with the hypothesis that the AKT1 (E17K) mutation and the PIK3CA mutation are mutually exclusive. The coexistent mutations of AKT3 and PIK3CA in one sample suggest that some types of AKT mutations (non-E17K) might coexist with PIK3CA mutations to enhance the activation of the PI3 kinase -AKT pathway. Further analyses are necessary to clarify the frequency of coexistent mutations in AKT1 (E17K), AKT2/3 and other mutations.
Their current data and our data suggest that the PI3 kinase -AKT pathway is prevalently activated in endometrial cancer through various genetic alterations and their combinations. Further analyses in AKT, PIK3CA and other PI3 kinase-AKTrelated genes would be helpful to comprehensively understand the mechanism of activation in this pathway and to use PI3K-targeted therapies in various types of cancer.
We thank Dr Dutt and colleagues for their recognition of our work.