Pathophysiology of Colorectal cancer

Ji Keon LOOI

Polyps
•small protrusion on the end of a slim stalk
•can grow out of the membranes lining various areas of the body.
•grow either singly or in clusters.
•Mostly benign
•Most cases of colon cancer begin as small, non-cancerous (benign) clumps of cells called adenomatous polyps. Over time some of these polyps become colon cancers.
•Others: hyperplastic, inflammatory polyps

Colon Cancer and Polyp

Background of Colorectal Cancer
•Vast majority of colorectal cancers are adenocarcinomas – 95%
•Arises from preexisting adenomatous polyps that develop in the normal colonic mucosa
•Associated with discrete molecular genetic alterations
RevisionPathogenesis of cancer
•Tumour suppressor gene
•Oncogene

Properties of Cancer Cells:
•evading apoptosis
•self-sufficiency of growth factors
•increased cell division rate
•altered ability to differentiate
•ability to invade neighbouring tissues (metastasis)
•ability to promote blood vessel growth (angiogenesis)

Genetic Basis for Colon cancer
•Mutations of APC (adenomatous polyposis coli) gene
–familial adenomatous polyposis (FAP), and
–Sporadic colorectal cancer

•The protein encoded by the APC gene targets the degradation of beta-catenin, a protein component of a transcriptional complex that activates growth-promoting oncogenes, such as cyclin D1 or c-myc.

More about genetics of colon cancer
•Leads to imbalance in genomic DNA methylation
•global hypomethylation è oncogene activation
•regional hypermethylation è silencing of tumor suppressor genes
•Bcl2 over-expression è inhibition of cell death signaling (antiapoptotic)è colorectal cancer development

Familial adenomatous polyposis (FAP)
•autosomal dominant
•less than 1% of all colorectal cancers and has an incidence of 1 in 10,000
•presence of 100 or more tubovillous adenomas in the colon
•almost all of gene carriers have polyps by 40 yo. Untreated polyps è malignant transformation

Autosomal Dominant Inheritance

Attennuated Familial Adenomatous Polyposis
•a milder version of FAP
•less than 100 colon polyps
•autosomal dominant
•very high risk of developing colon cancers at young ages.
•Also at risk of gastric polyps and duodenal polyps

Hereditary non­polyposis colon cancer
•gene carriers will develop a small number of tubovillous adenomas, but not more than 100
•Mismatch repair genes
•Knudson’s two hit hypothesis
–Failure to repair mutations in tumour suppressor genes è adenoma carcinoma

•Also at risk of developing uterine cancer, stomach cancer, ovarian cancer, and cancers of the ureters, and the biliary tract
Colorectal Cancer

Thank you
•Any Questions?