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Silver A.,Blizard Institute for Cell and Molecular science | Sengupta N.,Blizard Institute for Cell and Molecular science | Propper D.,St. Bartholomew's Hospital | Wilson P.,St. Bartholomew's Hospital | And 7 more authors.
International Journal of Cancer | Year: 2012

Aberrant DNA methylation, microsatellite instability (MSI) and chromosomal instability (CIN) are well-characterised molecular features of sporadic colorectal cancers (CRCs). In addition to CpG island methylator phenotype (CIMP) associated with MSI, an intermediate methylation subgroup is also a feature of non-MSI cancers. A large proportion of CRCs have no evidence of either MSI or CIN, here called Microsatellite and Chromosomal Stable (MACS), and require their methylation profile to be established. The clinical and molecular features of 170 sporadic CRC patients were investigated and stratified into MSI, CIN and MACS groups. MACS were most often found in the left colon and had a significantly lower BRAF mutation frequency (p < 0.001) compared with MSI. MACS had better survival [hazard ratio (HR) = 0.244, p = 0.017] compared with CIN, but were similar to MSI. The methylation status of 1,505 CpG loci from cancer-related genes was analysed in a subset of CRCs (n = 44 normal-tumour pairs) and compared with CIN, MSI and MACS status. Using two-way hierarchical clustering, three subgroups were identified, which associated with CIN, MSI and MACS status. Using significance analysis of microarray, 16 CpG loci demonstrating methylation changes associated with MACS were identified. A combination of six loci identified MACS with 81% sensitivity and 93% specificity. This result now requires independent validation. Hypomethylation of a CpG locus within the sonic hedgehog (SHH) promoter correlated with increased gene expression and was associated significantly with MACS cancers. In conclusion, we propose that MACS have distinct clinicopathological features and can be distinguished from other CRCs by a specific set of methylation loci. Copyright © 2011 UICC.

Pitiyage G.N.,Queen Mary, University of London | Lim K.P.,University of Bristol | Gemenitzidis E.,Queen Mary, University of London | Teh M.-T.,Queen Mary, University of London | And 6 more authors.
Journal of Oral Pathology and Medicine | Year: 2012

Oral submucous fibrosis (OSMF) is associated with paan chewing, altered collagen metabolism, inflammation and the upregulation of numerous cytokines. OSMF fibroblasts accumulate senescent cells at an increased rate because of increased reactive oxygen species production and DNA double-strand breaks (DDBs), generated intrinsically by damaged mitochondria. This results in a reduced replicative lifespan. However, it is still unclear which other changes are intrinsic to the fibroblasts and associated with OSMF rather than the paan chewing habit or the OSMF environment. Both the oral epithelium and the mesenchyme have elevated levels of TGF-β1 in OSMF in vivo. However, in cultured fibroblasts, secreted levels of TGF-β1, other cytokines and the matrix metalloproteinases 1 and 2 showed no association with OSMF. In contrast, the tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-2, were increased in 10/11 OSMF fibroblast cultures relative to normal and non-diseased paan user controls. OSMF fibroblast collagen levels were normal. TIMP levels correlated with replicative lifespan of the cultures but not with the presence of senescent cells, as senescent cell depletion in OSMF fibroblast cultures did not result in a reduction in either TIMP-1 or TIMP-2. However, the introduction of unrepairable DDBs into normal oral fibroblasts by ionizing radiation increased TIMP-1 and TIMP-2 secretion by two-fold and seven-fold, respectively, within 5days, replicating early senescence and the elevation seen in OSMF cultures. Therefore, increased fibroblast TIMP-1/2 levels could be early disease-specific markers of OSMF onset, DDBs and ageing and may have clinical significance, as OSMF can be reversed in its early stages. © 2012 John Wiley & Sons A/S.

Nicholson A.M.,University of Oxford | Nicholson A.M.,Queen Mary, University of London | Graham T.A.,London Research Institute | Simpson A.,London Research Institute | And 12 more authors.
Gut | Year: 2012

Background: Little is known about the stem cell organisation of the normal oesophagus or Barrett's metaplastic oesophagus. Using non-pathogenic mitochondrial DNA mutations as clonal markers, the authors reveal the stem cell organisation of the human squamous oesophagus and of Barrett's metaplasia and determine the mechanism of clonal expansion of mutations. Methods: Mutated cells were identified using enzyme histochemistry to detect activity of cytochrome c oxidase (CCO). CCO-deficient cells were laser-captured and mutations confirmed by PCR sequencing. Cell lineages were identified using immunohistochemistry. Results: The normal squamous oesophagus contained CCO-deficient patches varying in size from around 30 mm up to about 1 mm. These patches were clonal as each area within a CCO-deficient patch contained an identical mitochondrial DNA mutation. In Barrett's metaplasia partially CCO-deficient glands indicate that glands are maintained by multiple stem cells. Wholly mutated Barrett's metaplasia glands containing all the expected differentiated cell lineages were seen, demonstrating multilineage differentiation from a clonal population of Barrett's metaplasia stem cells. Patches of clonally mutated Barrett's metaplasia glands were observed, indicating glands can divide to form patches. In one patient, both the regenerating squamous epithelium and the underlying glandular tissue shared a clonal mutation, indicating that they are derived from a common progenitor cell. Conclusion: In normal oesophageal squamous epithelium, a single stem cell clone can populate large areas of epithelium. Barrett's metaplasia glands are clonal units, contain multiple multipotential stem cells and most likely divide by fission. Furthermore, a single cell of origin can give rise to both squamous and glandular epithelium suggesting oesophageal plasticity.

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