There is a familial risk of cancer and there are two main forms:
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and Familial adenomatous polyposis (FAP).
FAP have mutations in the APC tumour suppressor gene. The clinical pattern is that there are over 100 adenomas in the colon by the age of 30- by 45 they have developed colorectal cancer.
HNPCC is a mutation in mismatch repair. In DNA replication sometimes there are random slips in the bases, in HNPCC there is no mechanisms to correct these slips. MMR mutation can also be indicated in other kinds of cancer. The cancer usually develops in the right side of the colon and there may be a Crohn's type reaction.
The criteria for diagnosis are Bethseda and Amsterdam 1 and 2. Small errors in the genome are not repaired and there tends to be two hits in the MMR gene- MLH1 and MSH2 are usually the ones affected. The chromosomal loss or MMR instability affects many areas.
Inflammatory bowel disease can predispose to cancer. The risk of cancer depends on the duration of time you have had the inflammatory bowel disease. There is an increased risk of 18% after 30 years. Anything that changes the colon cells can promote colorectal cancer.
Risk factors:
Older age
Male
Cholecystectomy
Uretocholic anastamosis
Female hormonal factors
Red meat/Processed meat
Calcium
Sedentary
Obesity
Diabetes
Radiation
Alcohol
History of polyps
Previous colorectal/small bowel/ breast cancer
Colorectal cancer develops in a series of histological stages characterised by mutations in different oncogenes and tumour suppressor genes. For example, hyperplasia, adenoma and then carcinoma. There are usually around 4-6 mutations that occur to develop into a malignancy.
- k-Ras mutations are found in 35% of cancers as it increases cell growth.
- TGF-B pathways trigger SMAD2/4 which encode proteins that cause apoptosis (chromosome 18)- 60% of colorectal cancer has this. SMAD4 is indicated in juvenile polyposis.
- WNT- B-catenin pathway - B-catenin causes the cell to move into S phase and so there is more proliferation. The WNT usually signals the cell to inhibit APC (TSG) which usually suppresses B-catenin. The lack of suppression leads to the proliferation.
In carcinogenesis there needs to be genomic instability. Normal cells stop moving forward in the cell cycle if there's damage, so losing p53 is very important in lots of cancers invading. The cell cycle retardation is not occuring.
Chemotherapy is used in colorectal cancer. In people around age 60, if less nodes are involved this is much more effective. As there are more nodes involved this becomes less effective. The chemotherapy regime changes from 5-FU. Surgery may be used to try and remove the cancer. However, when it has metastasised this will be less useful.