dc.contributor.author | Dawkins, Joshua Benjamin Newton | |
dc.date.accessioned | 2017-06-27T12:25:31Z | |
dc.date.available | 2017-06-27T12:25:31Z | |
dc.date.issued | 2017-03-20 | |
dc.date.submitted | 2017-06-27T12:45:44.658Z | |
dc.identifier.citation | Dawkins, J.B.N. 2017. Aberrant downstream mechanisms following depletion of KMT2C and KMT2D in Pancreatic Ductal Adenocarcinoma. Queen Mary University of London | en_US |
dc.identifier.uri | http://qmro.qmul.ac.uk/xmlui/handle/123456789/24591 | |
dc.description | Phd | en_US |
dc.description.abstract | Genomic sequencing of pancreatic ductal adenocarcinoma (PDAC) tumours has
highlighted the existence of wide genetic diversity alongside frequent mutations in
KRAS, TP53 and SMAD4. Within this heterogeneity many components of the epigenetic
machinery are mutated, including the histone H3 lysine 4 methyltransferases KMT2C
and KMT2D, which are frequently subject to mutation and can identify patients with a
more favorable prognosis. In this thesis low expression of KMT2C and KMT2D were
shown to also define better outcome groups, with median survivals of 15.9 vs 9.2
months (p = 0.029), and 19.9 vs 11.8 months (p = 0.001) respectively. Experiments
across eight human pancreatic cell lines following their depletion suggest that this
improved outcome may be due to attenuated cell proliferation, with decreased
progression of cells from G0/G1 observed upon KMT2D loss. Whole transcriptome
analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and
124 differentially expressed genes respectively, with 19 common to both. Gene set
enrichment analysis revealed a significant downregulation of genes relating to cell-cycle
pathways, confirmed by interrogation of the International Cancer Genome Consortium
and The Cancer Genome Atlas PDAC data series. Furthermore, these experiments
highlighted a potential role for NCAPD3, a subunit of the condensin II complex, as a
PDAC outcome predictor across four patient gene expression series. Alongside this,
Kmt2d depletion in cells derived from murine models of pancreatic cancer led to an
increase in their response to the antimetabolites 5-fluorouracil and gemcitabine. Taken
together, the studies herein suggest that lower levels of this methyltransferase may
mediate the sensitivity of PDAC patients to particular treatments. Altogether, these data
suggest a potential therapeutic benefit in targeting these methyltransferases within
PDAC, especially in those patients that demonstrate higher KTM2C/D expression. | en_US |
dc.description.sponsorship | Cancer Research UK | en_US |
dc.language.iso | en | en_US |
dc.publisher | Queen Mary University of London | en_US |
dc.rights | The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author | |
dc.subject | pancreatic ductal adenocarcinoma | en_US |
dc.title | Aberrant downstream mechanisms following depletion of KMT2C and KMT2D in Pancreatic Ductal Adenocarcinoma | en_US |
dc.type | Thesis | en_US |