Patel Heena, Polanco-Echeverry Guadalupe, Segditsas Stefania, Volikos Emmanouil, McCart Amy, Lai Cecilia, Guenther Thomas, Zaitoun Abed, Sieber Oliver, Ilyas Mohammed, Northover John, Silver Andrew
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.
Int J Cancer. 2007 Dec 15;121(12):2668-73. doi: 10.1002/ijc.23028.
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.
人乳头瘤病毒（HPV）感染被认为是肛门鳞状细胞癌（ASCC）的一个重要病因，但不足以导致肿瘤进展。这种癌症在分子水平上了解甚少。我们利用迄今为止最大的病例队列，研究了ASCC发生发展的分子机制，特别是TP53、MDM2和AKT的作用。在我们的队列中，病毒感染发生率很高（73%，94/128），其中HPV16占感染病例的大多数（86%，81/94）。只有4%（5/119）的ASCC显示TP53（外显子5-8）突变，但观察到TP53核蛋白表达频率很高（91%，100/110）。尽管未发现MDM2突变且拷贝数正常，但TP53核积累与MDM2蛋白之间存在显著关联（p < 0.001）。66%（82/125）的ASCC中观察到磷酸化-AKT的细胞积累，并且MDM2核积累与活化的AKT之间存在关联（p < 0.001）。我们观察到PIK3CA的拷贝数增加频率很高（47%），以及一些编码序列突变（4%）。PIK3CA的扩增与磷酸化-AKT的存在相关（p = 0.008）。病毒感染与TP53核积累之间无关联（p = 0.5）。然而，发现感染与MDM2核染色之间以及感染与活化的AKT之间存在显著关联（分别为p = 0.04，p = 0.01）。我们提出，AKT的激活可能通过PI3K-AKT途径，是ASCC肿瘤发生的一个重要组成部分，有助于MDM2和TP53在细胞核中的积累。
