13. Cancer as a disease - Colorectal Cancer Flashcards
1
Q
Describe colonic physiology and function.
A
- Extraction of water from faeces (electrolye balance)
- Faecal reservoir (evolutionary advantage)
- Bacterial digestion for vitamins (e.g. vitamin B and K)
2
Q
Describe the colonic anatomy.
A
- This is normal large bowel
- The mucosa is folded but it is smooth
- There is a thick muscle layer (muscularis)
- Cancers in the colon are adenocarcinomas (in the glandular epithelium)
- Cells divide in the crypts where the stem cells are found, then they are shunted up to the top of the villus where they are shed
3
Q
Describe the turnover of colonic epithelium.
A
- 2-5 million cells die per minute in the colon
- The high rate of proliferation means that the cells are vulnerable
- APC (adenomatous polyposis coli) gene product reduces the risk of mistakes during replication
- APC gene mutation can cause cell proliferation
- Normally there are protective mechanisms to eliminate genetically defective cells by:
- Natural loss
- DNA monitors
- Repair enzymes
4
Q
Define polyp.
A
any projection from a mucosal surface into a hollow viscus, and may be hyperplastic, neoplastic, inflammatory, hamartomatous etc.
5
Q
Define adenoma.
A
benign neoplasm of the mucosal epithelial cells
6
Q
Name the colonic polyp types.
A
- Metaplastic/Hyperplastic
- Adenomas
- Juvenile, Peutz Jeghers, Lipomas (don’t really need to know about these ones)
7
Q
Describe hyperplastic polyps.
A
- Very COMMON
- < 0.5 cm
- 90% of all colonic polyps
- There are often multiple polyps
- NO malignant potential
- 15% have K-Ras mutations
8
Q
What are the types of colonic adenomas?
A
- Tubular- 90% (>75% tubular)
- Tubulovillous- 10% (25-50% villous)
- Villous (>50% villous)
- IMPORTANT: the more villous it is the worse it is
9
Q
Describe the shape of adenomas.
A
- Pedunculated adenomas are on a stalk - it looks a bit like a tree
- Sensile adenomas are flat and raised - look like a nice carpet
- Both of these can be tubular, tubulovillous or villous
10
Q
Describe the microscopic structure of adenomas.
A
- NOTE: adenomas are not malignant but they are heading towards being malignant. They are dysplastic but they haven’t invaded through the basement membrane
-
Tubular Adenomas
- Columnar cells with nuclear enlargement, elongation, multi-layering and loss of polarity
- Increased proliferative activity
- Reduced differentiation
- Complexity/disorganisation of architecture
-
Villous Adenomas
- Mucinous cells with nuclear enlargement, elongation, multi-layering and loss of polarity.
- Exophytic - frond-like extension
- Rarely may have hyper-secretory function and result in excess mucus discharge and hypokalaemia
11
Q
Define dysplasia.
A
- Literal meaning = ‘bad growth’
- Abnormal growth of cells with some features of cancer
- Indefinite - has low grade and high grade
12
Q
Describe adenomatous polyposis coli (APC).
A
- NOTE: ulcerative colitis can lead to dysplasia
- There are some conditions that lead to increased numbers of polyps
- The most famous condition that increases the number of polyps is familial adenomatous polyposis (FAP)
- A lot of people have colonic polyps but in FAP there are thousands and thousands of polyps
- 5q21 gene mutation
- Site of mutation determines clinical variants (classic, attenuated, Gardner, Turcot etc.)
- Many patients have prophylactic colectomy
- The link between APC and colon cancer allowed the discovery of the adenoma-carcinoma sequence
13
Q
Describe the progression from adenoma to carcinoma
A
- MOST colorectal cancers arise from adenomas
- Residual adenoma in about 10-30% of colorectal cancers
- Adenomas and cancer have similar distribution
- Adenomas usually precede cancer by 15 years
- Endoscopic removal of polyps decreases the incidence of subsequent colorectal cancer
14
Q
Describe the genetic pathways in colorectal cancer.
A
-
Adenoma Carcinoma Sequence
- APC = best known gene that is damaged.
- Others - K-Ras, Smads, p53, telomerase activation
-
Microsatellite Instability
- Microsatllites are repeated sequences that are prone to misalignment
- Some microsatellites are in coding sequences of genes which inhibit growth or apoptosis (e.g. TGFbR11)
- Mis-match repair genes (MSH2, MHL1 + 4 others) - recessive genes requiring 2 hits - without this, there is a very elevated risk of cancer
- HNPCC - microsatellite instability (Defects in DNA repair)
15
Q
What dietary factors affect colonic cancer? How does this relate to the incidence in different countries?
A
- High in USA, Eastern Europe and Australia
- Low in Japan, Mexico and Africa
- Dietary factors make a difference:
- High fat
- Low fibre
- High red meat
- Refined carbohydrates
- NOTE: cooking at high temperatures can alter the chemical structure, producing chemicals that can cause mutagenesis
- Food contains carcinogens
- It also contains AntiCancer Agents
- Bacteria modify food residues
16
Q
What is the link between dietary deficiencies and colorectal cancer?
A
-
Folates
- Folates are important co-enzymes for nucleotide synthesis and DNA methylation
-
MTHFR
- Deficiency leads to disruption in DNA synthesis causing DNA instability (strand breaks and uracil incorporation) - this leads to mutation
- Decreased methionine synthesis leads to genomic hypomethylation and focal hypermethylation- this can have gene activating and gene silencing effects
25
Q
What are the treatment options for colorectal cancer?
A
