Lecture 6 - multi-step tumorigenesis

Question 1

structure of the intestinal epithelium

Answer 1

1. differentiated cells (enterocytes, goblet cells, endocrine cells)
2. Transit amplifying (TA) cells: Lgr5+ ISCs that divide into 16-32 differentiated cells
3. Paneth cells: secrete lysozyme
4. +4 cells: very slowly dividing cells
5. Crypt base columnar (CBC) cells: Lgr5+ ISCs give rise to all lineages of IECs

IEC: intestinal epithelial cells

Question 2

what is the sequence of the histopathological alterations of cancer?

Answer 2

cell with mutation –> hyperplasia –> dysplasia –> in situ cancer –> invasive cancer

Question 3

Histological evidence that adenoma differs from carcinoma

Answer 3

they sometimes have clear borders
carcinoma grows out of adenomas

Question 4

clinical proof that adenoma is the prescursor of carcinoma

Answer 4

removing adenomatus polypses reduces chance of developing colon carcinoma

Question 5

lineage tracing proof that adenoma is the prescursor of carcinoma

NSCLC

Answer 5

all originated from same rare p53 mutation
- LLL (left lower lobe) became squamous cell cancer
- LUL (left upper lobe) became less apparent

Question 6

what is the LOH?

loss of heterozygosity

Answer 6

a cross chr event that results in the loss of the entire gene and the surrounding chr region

Question 7

what does the LOH mean?

eg of cancer

Answer 7

• common occurrence in cancer
• indicates the absence of TSG in the loss region

BRCA1 and BRCA2 (breast cancer)
RB1

Question 8

what are the mechanisms of LOH

Answer 8

• chr loss
• deletion
• unbalanced translocation
• loss of reduplication
• mitotic recombination
• point mutation

Question 9

Colon cancer progression

Answer 9

normal epithelium -(LOH ch5q: APC TSG)-> hyperplasia epithelium –> early adenoma -(activation of KRAS)-> intermediate adenoma -(LOH ch18q: Smad4)-> late adenoma -(LOH ch17p: TP53)-> carcinoma

activation of KRAS and LOH at ch17p for TP53 are mutually exclusive

Question 10

3 roles of DNA methyation in cancer

Answer 10

1. CpG island in promoter
2. hypermethylation of cytosine at CGI –> silent gene expression
3. hypomethylation cytosine at CGI –> activates gene expression (KRAS)