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home - Colon - Colorectal and Anal Cancer - Colorectal Cancer Molecular Pathways Written by Dr Sebastian Zeki

Knows the pathology of benign and malignant tumours of the colon
and rectum
Has awareness of the molecular genetics of colorectal
carcinogenesis and the adenoma-carcinoma sequence
Knows the range of predisposing conditions including inherited
syndromes and acquired colonic diseases
Knows the range of clinical presentation and the means of
diagnosis, investigation, management and follow-up
Knows the strategy for prevention including procedures for

Uses clinical assessment and selects investigations to reach a rapid
conclusion as to whether a patient might have colorectal cancer and
arranges timely investigation.
Refers the patient to the multi-disciplinary team CbD, mini-CEX,

Shows ability to react to possible diagnosis of malignancy in a timely

Communicates with patient and family in a sympathetic and
understanding manner, explains next steps, involves other health
professionals (including the GP) as appropriate

Colorectal Cancer Molecular Pathways

Takes around 10 yrs for a small polyp to become a cancer The TP53 gene It arrests the cell cycle.In 60 % of CRCs, TP53 inacti-vation occurs by a mutation of one allele followed by loss of the remaining wild type gene.TP53 mutations are a late event.It may represent an earlier event in IBD-related CRC. The APC geneIts function is to prevent Beta- catenin accumulation and therefore stop the proliferation inducing tran-scription factor Tcf-4.Somatic mutations in both alleles are present in 80 % of sporadic CRCs.A single germline mutation in this gene is responsible for FAP.It is an early event in tumori-genesis normally. The K-Ras GeneRas oncogenes regulate cellular signal transduction.Mutations are found in up to 50 % of sporadic CRCs and 50 % of colonic adenomas >1cm.It is rarely seen in smaller adeno-mas.It is more common in proximal colon cancers than in more distal colorectal primaries. Phenotypic variants of MSI based upon the number of loci demonstrating: MSI low (MSI-L)-characteristic of HNPCC ,but also found in African-American CRCMSI high (MSI-H)- characteristic of sporadic Sporadic Colorectal Cancer Pathways The MSI pathway characterized by CIMP(CpG Island hyperMeth-ylation Phenotype)= CRC with high frequency of methylation of some CpG islands of hMLH1, a DNA mismatch repair (MMR) gene Hereditary Forms FAP HNPCC Li-Fraumeni Syndrome The chromosomal instability (CIN) path-way Chromosomal instability (CIN) results from "gain of function" mutations.These may result either in activation of growth promoting pathways including oncogenes or diminished activity of tumor suppressor genes or apoptotic pathways.In both cases, there is a gain in functional activity. Normal epithelium Early adenoma Intermediate adenoma Late adenoma Late adenoma Carcinoma Carcinoma Metastasis Hypomethylation 1p lossAPCBeta cateninWnt pathway Kras MAPK pathway 18q lossDCCSMAD2/4 TGFBeta pathway TP53 TGFIIbBAX TCF4WISP3 hMLH1hMSH 2/3/6 15% microsatellite unstable tumours (MSI) 85% chromosome unstable tumours Sporadic MSI CRC characteristics:Proximal colon.Greater mucinous component.Contain lymphocytic infiltration.More poorly differentiated. Written by Dr Sebastian Zeki

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