Lecture 31 Flashcards
What is the general epidemiology of colorectal carcinoma?
8.5% of all cancers
Occurs in the one cell thick lining of colon or rectum and usually develops via adenomas
What is the evidence that adinomas transform into carcinomas?
Adenomas and carcinomas have the same distribution within the colon
Adenomas often contain foci of invasive cancer while carcinomas are associated with areas of adenoma
There is a temporal link where adenoma appearance precedes carcinoma by 10-15 years which is reduced if polypectomy is performed
Hereditary CRCs preceeded by adenomas
Carcinogen treated rats develop adenomas before carcinomas
What is adenomatous polyposis coli?
A condition where there is a large number of adenomas, while each has only a low number of becoming a cancer, the large numbers make cancer development unavoidable
What is hereditary non-polposis colorectal cancer?
Few adenomas are formed but they have a high probability of turning into a cancer
What are the four pathways to Colorectal Cancer?
Typically associated with genetic instability using the routes of chromosomal mutation, DNA base sequence mutations when mismatch repair is non-functional
Deficiencies in methylation alternatively CRC can be induced by chronic inflammation
How does chromosome instability lead to colon cancer?
Loss of DNA methylation, loss of telomeres both of which can generate aneuploidy and chromosomal rearrangements
How do DNA base sequence changes lead to colon cancer?
If mismatch repair is disabled then there are frequent substitutions, insertions and deletions, particularly in the microsatellites, resulting in microsatellite instability
What is HNPCC?
A condition which arises from hereditary mutations in the genes responsible for Mismatch repair
How do deficiencies in methylation cause colon cancer?
Cause an epigenetic route cancer via the CpG island methylation phenotype, this results in the silencing of TSGs and MMR genes
How does chronic inflammation lead to colon cancer?
Chronic inflammation occurs in ulcerative colitis leading to an increase in free radicals creating a genotoxic environment leading to ulceration and dysplasia of the epithelial layer leading to cancer without prior adenoma stage
Why are the crypts in the colon typically monoclonal?
At each crypt base there is a small number of stem cells these divide infrequently to give rise to progenitor cells which give rise to all cells lining the crypt
What is the distribution of regulator proteins in the crypt of the colon?
Stem Cells produce nuclear beta catenin and Myc
Progenitor cells produce Myc
Termially differentiated cells produce both APC and p21
What is the earliest visible sign of colorectal cancer development?
Unicryptal adenoma where an increase in stem cells results in microadenomas
What are the featucres of microadenomas?
Contain few to many crypts Enlarged, abnormally shaped lumens Show dysplastic change Show expansion of proliferative zone Expression of Myc but not p21 in upper crypt
What is the genetic lesion that can initiate cancer development?
A translocation with a breakpoint at c5q21, where the APC susceptibility locus is, adenomas develop when both functional copies of APC are lost
