Microsatellite Insability and Precursor Colonic Lesions

Question 1

What causes familial adenomatous polyposis coli?

Answer 1

Inactivation of APC gene.

Initiates thousands of adenomas (most don’t progress to cancer but individual chance overall greatly increased).

Question 2

What are the main mechanisms of instability causes CRC?

Answer 2

Microsatellite instability (think hereditary)
DNA hypermethylation (think acquired)

Question 3

What are micro satellites?

Answer 3

Short repeat sequences of DNA throughout genome; genetic “fingerprint”.

Question 4

What is micro satellite instability?

Answer 4

Variation in length of sequence of micro satellites.
Not exact replica between cell generations.
Indicates error in “proofreading” of DNA
Seen in 15-30% of sporadic CRCs.

Question 5

What is the DNA mismatch repair system?

Answer 5

multi protein complex responsible for correction of errors arising during cell division.
Proteins include hMLH1, hMSH2 etc.
Require inactivation of both alleles to lose functional activity.

Question 6

How can errors in mismatch repair system be tested for?

Answer 6

Immunohistochemistry.
Tests for MMR proteins.
Specificity 100%

Question 7

What is CpG island methylator phenotype?

Answer 7

Methylation of promoter region of MMR genes can lead to their silencing and increased micro satellite instability.
Tumours may be CIMP low or CIMP high.

Question 8

Describe the histopathological appearance of CRC.

Answer 8

Enlarged, hyper chromatic nuclei, nuclear atypia.

Cancer: necrosis in glands, induce own stroma, cross tissue layers.

Question 9

What are sessile serrated polyps?

Answer 9

RHS polyps containing MSI that may give rise to CRC

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