title: Activation of AKT and nuclear accumulation of wild type TP53 and MDM2 in anal squamous cell carcinoma.
abstract: Human papilloma virus (HPV) infection is considered as an important aetiological factor for anal squamous cell carcinoma (ASCC) but is not sufficient for tumour progression. This carcinoma is poorly understood at the molecular level. Using the largest cohort of cases to date we investigated the molecular mechanisms underlying ASCC development, in particular the roles of TP53, MDM2 and AKT. Viral infection in our cohort occurred at high frequency (73%, 94/128) with HPV16 accounting for the majority (86%, 81/94) of infected cases. Only 4% (5/119) of ASCCs showed TP53 (exons 5-8) mutations, but a high frequency (91%, 100/110) of nuclear protein expression of TP53 was observed. There was a significant association (p < 0.001) between nuclear accumulation of TP53 and MDM2 protein although no MDM2 mutations were found, and copy number was normal. Cellular accumulation of phosphorylated-AKT was observed in 66% (82/125) of ASCCs and an association demonstrated between nuclear accumulation of MDM2 and activated AKT (p < 0.001). We observed a high frequency of copy number gain at PIK3CA (47%), and some coding sequence mutations (4%). Amplification of PIK3CA was associated with presence of phosphorylated-AKT (p= 0.008). There was no association between virus infection and TP53 nuclear accumulation (p = 0.5). However, a significant association was found between infection and MDM2 nuclear staining, and between infection and activated AKT (p = 0.04, p = 0.01, respectively). We propose that activation of AKT, possibly through the PI3K-AKT pathway, is an important component of ASCC tumorigenesis that contributes to MDM2 and TP53 accumulation in the nucleus.
authors.affiliation: Colorectal Cancer Genetics, Institute for Cell and Molecular Sciences, Blizard Building, Barts and The London, Queen Mary's School of Medicine and Dentistry, 4 Newark St., Whitechapel E1 2AT, United Kingdom.
authors.forename: Heena
authors.initials: H
authors.lastname: Patel
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Polanco-Echeverry
authors.forename: Stefania
authors.initials: S
authors.lastname: Segditsas
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Volikos
authors.forename: Amy
authors.initials: A
authors.lastname: McCart
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lai
authors.forename: Thomas
authors.initials: T
authors.lastname: Guenther
authors.forename: Abed
authors.initials: A
authors.lastname: Zaitoun
authors.forename: Oliver
authors.initials: O
authors.lastname: Sieber
authors.forename: Mohammed
authors.initials: M
authors.lastname: Ilyas
authors.forename: John
authors.initials: J
authors.lastname: Northover
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
mesh_terms: D000328:Adult; D000368:Aged; D052685:Alphapapillomavirus / Q000302:isolation & purification; D019943:Amino Acid Substitution; D001005:Anus Neoplasms / Q000235:genetics* / Q000821:virology; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000821:virology; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D027383:Papillomaviridae / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014412:Tumor Virus Infections / Q000150:complications / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt