Abstract
The serine-threonine kinase AKT1 is a central player in the oncogenic pathway controlled by PI3K. Recently, a somatic mutation in AKT1 (E17K) has been detected in breast, colorectal, lung and ovarian cancers. The E17K change results in constitutive AKT1 activation and induces leukaemia in mice. We determined the occurrence of the E17K variant in a panel of 764 tumour samples. These included breast, lung, ovarian, colorectal and pancreatic carcinomas as well as melanomas and glioblastomas. Despite the fact that these tumours are known to bear alterations in genes involved in the PI3K signalling pathway, AKT1E17K was detected only in breast (16/273), colorectal (1/88) and lung (1/155) cancers. Within the neoplasms of breast origin, the AKT1E17K variant was mutually exclusive with respect to the PIK3CAE454KorH1047R alleles and was present only in ductal and lobular histotypes. Our results, showing that AKT1 mutations seem to occur in a tissue-specific fashion have basic and clinical implications. First, the activity of mutated AKT1 in oncogenic PI3K signalling could be strictly dependent on the cell and tissue milieu. Second, therapeutic efforts aimed at selective targeting the AKT1E17K variant could be effective mainly in specific cancer types.
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Acknowledgements
We thank Dr T Hulsebos and Professor Dr Troost for making glioblastoma tumour samples available. We thank Dr S Pilotti and Dr M Pierotti for providing the colorectal cancer samples. This work was supported by grants from Italian Association for Cancer Research (AIRC, A Bardelli), Italian Ministry of Health, Regione Piemonte (A Bardelli), Italian Ministry of University and Research and Association for International Cancer Research (AICR-UK, A Bardelli), EU FP6 contract 037297 (A Bardelli) and MolDiagPaca (AS). FB is supported by a Netherlands Genomic Initiative Fellowship.
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