C82
Mutation analysis of PI3K-AKT pathway genes in anal squamous cell carcinoma and anal intraepithelial neoplasia
Alexandra Parker1, Cecilia Lai1, Guadalupe Polanco-Echeverry1, Stefania Segditsas2, Thomas Guenther3, Abed Zaitoun4, Mohammed Ilyas4, Andrew Silver1, Heena Patel1
1Institute of Cell and Molecular Science, Barts and The London, London, UK, 2London Research Institute, Cancer Research UK, London, UK, 3St Mark's Hospital, London, UK, 4Queens Medical Centre, Nottingham, UK
Anal squamous cell cancer (ASCC) is a devastating disease and sexually transmitted infection of mucosal human papilloma virus (HPV) is the major causal factor for pre-malignant anal intraepithelial neoplasia (AIN). AIN has parallels to cervical and vaginal intraepithelial neoplasia (CIN, VIN), which progresses from low-grade to high-grade and finally to invasive cancer. Currently, there is no means of identifying which benign tumours will progress to invasive carcinoma. Using the largest ASCC cohort to date (n=128), we have found that the majority of ASCCs show infection with HPV (84%), particularly type 16, and activation of the PI3K-AKT pathway (64%). Mutational analysis of pathway members has shown that amplification of the oncogene PIKC3A (46%) rather than point mutation of AKT1, 2 and 3 (3%) or PIK3CA (4%) to be the underlying molecular cause of pathway activation. An association was found between PIK3CA amplification, AKT activation and HPV infection (p<0.01). With a new panel of tissue samples containing low and high grade AINs and ASCC, we plan to define the point at which AKT is activated during tumour development and thereby establish whether the expression of AKT can be used as a marker for progression in the clinic. The PI3K-AKT pathway is clearly important in tumorigenesis and its investigation will add significantly to our knowledge of anal cancer biology and HPV-related cancers. Furthermore, ASCC may be a suitable target for PIK3CA antagonists now under investigation in other tumours.
