Abstract
BackgroundThe PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC) and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions.Methods186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires.ResultsMutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05). PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04). Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02) and poor differentiation (p < 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55).ConclusionThese data demonstrated the frequent occurrence (34.9%) of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage.
Highlights
The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the phosphatidylinositol 3 kinases (PI3K)/AKT signalling pathway
This variability in observed PTEN mutation frequencies relates to tumour genomic instability, with PTEN mutations having been described in 14-30% of colorectal cancers (CRC) with microsatellite instability (MSI-H) [9,14,15], but at very low frequencies (
The present study aimed to investigate the relationship between PTEN and PIK3CA mutations and loss of PTEN expression in 186 colorectal adenocarcinomas from the EPIC Norfolk cohort and clinicopathological features, lifestyle traits and dietary factors, as well as analysing PTEN expression negative CRC stratified by stage and tumour location
Summary
The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. The PI3K/AKT signalling pathway affects many cellular processes including cell proliferation, apoptosis and invasion [1]. Signal transduction through this pathway is mediated through conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol triphosphate (PIP3) by phosphatidylinositol 3 kinases (PI3K) following their activation, and this reaction is antagonised by phosphatase and tensin homolog, deleted on chromosome ten (PTEN) activity. In colorectal cancer (CRC), PIK3CA activating mutations have been described at frequencies of 10-20% [3,4,5,6], with two distinct regions, the helical and kinase domains, harbouring up to 80% of mutations [7]. Loss of PTEN expression has been reported at higher frequencies than mutation [12,15] with approximately 20-40% of CRC exhibiting loss of PTEN expression [16,17]
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