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Title: The role of p14 in Barrett's oesophagus and associated adenocarcinoma
Author: Huang, Y.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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The p14 tumour suppressor plays a central role in cancer by promoting p53­-mediated cell cycle arrest and apoptosis in response to oncogene activation. This mechanism provides an important barrier to tumourigenesis, but is abrogated in some cancers through loss of p14 expression. Somatic mutation of p14 is rare, but gene deletion and promoter methylation have been implicated as important mechanisms of gene silencing. However, the manner in which these and other events contribute to biallelic silencing of p14 during spontaneous tumour progression has not been addressed. We have examined the mechanism of p14 silencing in oesophageal adenocarcinoma, a cancer that displays a high frequency of p14 loss without homozygous deletion of the p 14 gene, and is a likely candidate for epigenetic silencing. A premalignant condition known as Barrett’s Oesophagus, increases the risk of adenocarcinoma by about 100 fold, and provides a rare model for multistep tumourigenesis not found in most other human cancers. We find that progressive loss of p14 expression during oesophageal cancer progression correlates with a novel sequence of epigenetic events that silence one allele of p14 in Barrett’s Oesophagus through p14 exon1β methylation, followed by silencing of the remaining allele in adenocarcinoma through histone H3- lysine 9 trimethylation without CpG methylation. 5-aza-2’-deoxycytidine (5-aza-CdR) reverses both modifications and activates both alleles. Overexpression of p14 with adenovirus showed a strong tumour inhibition effect in an in vitro and in vivo model.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available