Deegan colorectal ca

Question 1

Describe 2 anti-cancer mechanisms of p53

Answer 1

Response to DNA damage
- When DNA is damaged, P53 becomes activated and responds by activating P21
-P21 can then inhibit cyclin-CDK complexes thereby preventing progression of that cell through the cell cycle.
-This allows for P53 to promote expression of DNA repair genes.

Promotes apoptosis
- If DNA damage is irreversible P53 can induce pro-apoptotic gene expression.
- These pro-apoptotic mediators such as BAX can then release cytochrome C from the cell mitochondria which results in downstream cascade leading to cellular apoptosis.

Question 2

Explain how APC and KRAS genes normally function in mediating cellular proliferation

Answer 2

APC
- Tumour suppressor gene
-APC normally functions to bind to and degrade Beta-catenin which is a key upregulator of genes that drive cellular proliferation e.g. MYC and Cyclin D1.
-Mutations in APC gene results in accumulation of beta-catenin which translocates to the cell nucleus to upregulate these genes.

KRAS
- Oncogene
- KRAS gene encodes for a GTP-binding protein that binds to GTP forming an active conformation which increases the activity of the MAPK pathway which drives cellular proliferation
- KRAS mutation causes hyperactive GTP-binding protein which causes excessive activation of MAPK pathway.

Question 3

Outline how microsatellite instability plays a role in colorectal tumor-genesis

Answer 3

Microsatellites are regions in the genome of short, repeated DNA sequences. During DNA replication, these regions may experience errors in their sequence which are typically repaired through expression of DNA mismatch repair genes.

DNA mismatch repair gene mutation can result in accumulation of errors in these microsatellites which can become shorter or longer than usual thereby affecting normal protein function. This is called microsatellite instability.

2 examples of genes affected by MSI are:
(i) TGF-B II gene–> Normally functions to inhibit cellular proliferation of colonic epithelial cells. Therefore in mutation TGF-B genes, this function is lost.

(ii) BAX gene –> Normally promotes apoptosis by facilitating cytochrome C release from mitochondria, which activates caspase-mediated cell death. Therefore mutation in BAX gene results in loss of apoptosis.

Question 4

Describe the 3 histological patterns of adenomatous polyps

Answer 4

(1) Tubular adenomas
-Most common type
-These are typically small (<1cm), pedunculated polyps with > 75% of the architecture being branched tubular gland pattern.
-Lined by dysplastic columnar epithelium
-Low risk (<5% transform to cancer) unless >1 cm or with high-grade dysplasia.

(2) Villous adenomas
-1% of adenomas
-These are sessile growths with frond-like projections and lined with dysplastic glandular epithelium
-They contain >50% villous architecture.
-High risk of malignancy (>50% if >2cm)

(3) Tubulovillous adenomas
-10% of adenomas
-Combination of tubular and villous architecture
-Intermediate size (1-3 cm), can be pedunculated or sessile.
-intermediate risk of malignancy; risk increases if higher proportion of villous architecture.

Question 5

Name 3 features of polyps that determine likelihood of malignant change

Answer 5

(1) Size (most important feature)
(2) Histological architecture –> higher risk if sessile villous
(3) Degree of dysplasia –> usually found in villous areas

Question 6

Name 4 types of colonic polyps and the histological feature of each

Answer 6

(1) Hyperplastic
-Most common type of polyp that occurs sporadically.
-Non-neoplastic with no malignant potential
-Decreased epithelial turn over with accumulation of mature epithelial cells.
-Typically small (<5mm) and found on the surface of mucosal folds.

(2) Hamartomatous
-Rare and sporadically occuring
-Disorganised proliferation of hyperplastic mucosal epithelium and arborizing smooth muscle pattern
-Low risk of malignancy unless associated with genetic syndromes

(3) Adenomatous
-Neoplastic polyp
-Dysplastic glandular epithelium associated with a tubular, villous or tubulovillous architecture.
-Demonstrates usual dysplastic features e.g. nuclear hyperchromasia
-Malignant potential depends on the type, size and severity of dysplasia.

(4) Inflammatory
-Associated with conditions such as inflammatory bowel disease.
-Often called pseudopolyps
-Caused by regenerating mucosa bulging into colonic lumen

Question 7

Describe 4 differences between first intention and second intention wound healing

Answer 7

(1) Wound edges
-Closely opposed in first intention
-Farther apart in second intention

(2) Degree of inflammation
-2nd intention healing has more severe inflammation due to more extensive tissue destruction –> +++ macrophages and neutrophils required to clear debris

(3) Granulation tissue
- More granulation tissue/ fibroblast proliferation seen in 2nd intention in order to fill the defect

(4) Wound contraction
- more extensive contraction in 2nd intention to try heal the wound (+++ myofibroblasts)

(5) Epitheliazation
-Faster in first intention

(6) Scar formation
-More extensive fibrosis in scar formed during 2nd intention healing

Question 7

Describe the 4 phases of wound healing

Answer 7

(1) Hemostasis (sec-min)
-Platelet activation, aggregation and clotting factor release to form a fibrin clot at site.

(2) Inflammatory (0-3days)
-Inflammatory response with vasodilation, vascular permeability etc
-Neutrophils initially enter the site and release proteolytic enzymes to help degrade damaged tissue components and debris
-Macrophages then enter the phagocytose the debris.

(3) Proliferation (3 days to weeks)
-Granulation tissue is set down
-Fibroblasts are activated and deposit type III collagen
-VEGF release increases angiogenesis
-Epithelial cells begin to proliferate to regenerate the epidermis.
-Myofibroblasts begin wound contraction

(4) Remodelling
-Type III collagen is replaced by stronger type I
-Collagen cross linking increases wound tensile strength
-Capillaries regress as wound matures.
-Scar formation

Question 8

Describe the morphological characteristics of i) right-sided and ii) left-sided colorectal carcinoma and give two correspondent clinical consequences for tumours on each side.

Answer 8

Right sided
-Exophytic, polypoid or fungating with protrusion into the lumen
-mucinous/ colloid pattern
-Consequences: iron deficiency anemia, melena, vague symptoms e.g. fatigue, weakness.

Left sided
-Annular (ring like) and encircling with heaped up edges
-More ulceration and stenotic formation
-Consequences: constipation, obstruction (LLQ pain), occult bleeding