Colorectal Cancer Pathology
Colorectal cancer formation mostly involves cellular change from normal bowel mucosa to the benign precursor (adenoma) to carcinoma. The transitions are associated with characteristic genetic changes, such as alterations to APC, the DNA mismatch repair genes MLH1 & MSH2, KRAS and TP53. These genes also influence the regulation of proliferation, differentiation and apoptosis. This process is often associated with chromosomal instability, which we studied (with spectral karyotyping and array-comparative genomic hybridisation), to show loss or gain of gene copy number in colorectal tumours and using this approach we identified BRUNOL4, PARK2 and IRS2 as new genes in colorectal cancer development and progression.
To study the effects of mutated KRAS on intestinal tumour formation we used models with inherited APC mutation or deleted mismatch repair gene MSH2 and showed KRAS-mediated acceleration of intestinal tumourigenesis. Models of intestinal tumourigenesis were used to determine contributions to tumour formation by RASSF1A, GNAS, PARK2 and validation of SLX4/FANCP as a new Fanconi Anaemia gene. The Fanconi DNA repair pathway, known to repair DNA interstrand cross-links, was critically important in repairing DNA damage induced by alcohol/acetaldehyde and formaldehyde. These and other models continue to be used to identify and investigate other potentially novel intestinal cancer-related genes.
Principal Investigator and Professor of Pathology
|Mike Freya Mueller||Postdoctoral Research Fellow|
|Ying Zhou||Research Technician|
Molecular Pathology Node, Comparative pathology, Division of Pathology, Pathology & Phenomics Laboratory, Colorectal cancer, Endometrial cancer, Adenoma, Carcinoma, Cancer genes, Cancer Genomic Sequencing, Metastasis, Melanoma, Cancer Models
Image analysis (Definiens, ImageJ), Slide-scanning (2 Hamamatsu Nanozoomer slidescanners), Genomic, expression and model phenotype data: Whole genome sequencing, Whole genome sequencing, array-CGH, RNA-sequencing, expression arrays, immunohistochemistry (IHC – Bond III) and in-situ hybridisation (ISH – Bond RXM) platforms, Comparative pathology analysis, Tissue MicroArray, Hypoxystation, Faxitron X-ray Irradiation, ECMC, Tissue Governance tissue processing facilities