Edinburgh Pathology

Gastrointestinal Pathology

Colorectal cancer research represents the major gastrointestinal pathological research theme.

Colorectal carcinogenesis involves cellular transit from normal bowel mucosa usually via adenoma to carcinoma. The transitions are associated with characteristic genetic changes, such as alterations to APC (>80%), the DNA mismatch repair genes MLH1 & MSH2 (~15%), KRAS (~40%), and TP53 (>60%) amongst others, and these genes also influence the regulation of proliferation, differentiation, apoptosis and genomic stability.

Mutation of APC (which can be inherited in familial adenomatous polyposis coli syndrome or FAP) or loss of APC is seen in the development of conventional adenomas (tubular and villous in morphology) and this represents the major pathway of adenoma formation and predisposes to further progression to carcinoma. This process is often associated with chromosomal instability, which can be studied with spectral karyotyping or array-comparative genomic hybridisation (array-CGH) or Next Generation Sequencing (NGS).

Such techniques can pinpoint genes that consistently show loss or gain of copy number in colorectal tumours and using this approach we have identified BRUNOL4, PARK2 and IRS2 as new genes in colorectal cancer development and progression. DNA methylation investigations showed evidence of epigenetic silencing of cancer-related genes in these tumours, including MLH1 (leading to defective mismatch repair), MGMT, PTEN, DNMT3B and others involved in the WNT/APC/B-CATENIN signalling pathway.

A second (sessile serrated) pathway involves the transition of hyperplastic polyps via sessile serrated lesions/polyps to serrated adenomas on to carcinomas, often with evidence of associated microsatellite instability at high frequency due to DNA mismatch repair (MMR) deficiency. Defective MMR confers an increased mutation rate particularly in repetitive DNA sequences (the mutator or hypermutator phenotype) that generates variations in length of repetitive microsatellite sequences (microsatellite instability). This accounts for the susceptibility to cancer formation in colorectum, endometrium and other sites in Hereditary Non- Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome (LS) patients.

A new approach to diagnosis of suspected HNPCC/Lynch Syndrome (accounting for 3-4% all colorectal cancers) has been developed using tumour analysis for both abnormal mismatch repair protein expression by immunohistochemistry and microsatellite instability testing of tumour DNA.

Defective DNA mismatch repair is found in approximately 15% sporadic colorectal cancers and our studies of these have shown genetic changes in apoptosis-related genes, lower levels of chromosomal changes and altered mismatch repair protein expression (usually MLH1 silencing due to promoter hypermethylation). MSH2 and MLH1 are the most frequently mutated mismatch repair genes in HNPCC / Lynch kindreds. The regulation of apoptosis and contribution to colorectal carcinogenesis of defective mismatch repair were studied using in vivo models null for MSH2 and also null for both MSH2 and TP53, which showed that MSH2 can signal apoptosis via p53 after sensing DNA damage of mismatch type.

Principal Investigator

Prof Mark Arends

Current Phd projects

Intestinal tumour modelling and DNA damage: investigating the role of DNA mismatch repair in ethanol induced colorectal carcinogenesis