Term
| What are the 3 basic molecular events of the adenoma/carcinoma pathway? |
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Definition
3 pathways
1) Chromosomal instability
- LOH in genes like APC gene on 5q, K-ras on 12p, p53 on 17p, SMAD2 on 4 and 18q
- Aneuploid tumors
2) MIcrosatellite instability (MSI)
- Operative in HNPCC, involving mutations in DNA mismatch repair genes like MSH2 on 2[ and MLH1 on 3[
- Diploid tumors
3) CIMP, CpG island methylator phenotype
- Methylation of promotor region and transcriptional inactivation |
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Term
| What is the pathogenesis of Familial Adenomatous Polyposis (FAP)? |
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Definition
Rare (<1% of CRC) with intense proliferation of adenomas "carpeting" colon.
1) Germ-line mutation in APC (5q) gene, preventing phosphorylation of Beta-catenin.
2) Beta-catenin accumulates, enter nucleus and complexes with DNA-binding transcription factors that stimulate unbridled cell growth and neoplasia.
***Extra-intestinal manifestations include CHRPE (congenital hypertrophy of retinal pigment epithelium), osteomas and soft tissue tumors** |
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Term
| What is the pathogenesis of Hereditary Non-Polyposis Colorectal Cancer (HNPCC)? |
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Definition
Phenotype similar to sporadic cancer (no colon carpeting with polyps)
1) Defect is mismatch repair genes (MMR) that control fidelity of DNA replication
2) Mutations lead to abnormalities in DNA scattered about genome (ex: TGF-b) |
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Term
| Why is screening for CRC considered a grade A indication? |
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Definition
1) Early detection can facilitate treatment
2) Removing early polyps can Prevent cancer. |
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Term
| What % of people with FAP get CRC? |
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Definition
ALL OF THEM (100% penetrance of the APC mutation on 5q).
Remove the colon. |
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Term
| What types of adenomatous polyps are at high risk of developing CRC? |
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Definition
1) Those > 1cm
2) Villous or high-grade dysplasia |
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Term
What is the Fecal Occult Blood Test (FOBT) and how is it used in CRC?
What about the fecal immunochemical test (FIT)? |
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Definition
1) FOBT is screening method associated with 33% reduction in mortality and 20% decrease in incidence
2) FIT has better sensitivity for advanced adenoma and CRC without increasing false positive rate. |
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Term
| What is flexible screening sigmoidoscopy (FSG) and what is its utility? |
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Definition
Effective triage to colonoscopy (also less effective in proximal colon)
Effective endoscopy screening that reduces CRC incidence in proximal and distal cases but only mortality in DISTAL cases (stage IV cancer cause the mortality, and are usually found proximally) |
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Term
| What differentiated the right colon from the left colon in terms of CRC development? |
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Definition
1) Biological differences in methylation and microsatellite stability, as well as progression (more common in right)
2) Operator differences |
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Term
| What are the major criteria to evaluate biomarkers? |
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Definition
Characterize a point in time between carcinogen exposure and cancer development.
1) Variability of expression within phases of cancer
2) Ability to detect early
3) Risk association
4) Modifiable
5) Accessible
6) Quality control and operational procedures |
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Term
| What are the major etiologies of CRC? |
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Definition
1) IBD (20%)
2) HNPCC (4%)
3) FAP (1%)
4) Sporadic |
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