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Flashcards in Molecular Pathology - GI tract Deck (12)
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1

Describe the two pathways by which most colorectal adenocarcinomas arise.

Most follow the chromosomal instability pathway, featuring sequential mutations in K-RAS, APC, and TP53.

Some follow the hypermutable pathway, featuring deficient MMR activity with accumulation of missense mutations and indels in specific DNA sequence types.

2

What percentage of MSI colorectal cancers arise sporadically, and how many arise from hereditary syndromes?

About 12% arise sporadically. 3-4% arise from Lynch syndrome (& related syndromes)

3

Describe how IHC studies can identify which MMR protein is defective in hypermutable CRCs.

MLH1: Loss of MLH1 and PMS2 (heterodimer)

MSH2: Loss of MSH2 and MSH6 (heterodimer)

PMS2: Loss of PMS2 only

MSH6: Loss of MSH6 only

4

Describe how molecular studies can identify MSI.

Sequencing of microsatellite regions for changes in size; 2+ out of 5 indicates MSI-H, while 1 out of 5 indicates MSI-L (behaves like MS-S)

5

What signalling pathways are downstream of EGFR in the chromosomal instability pathway of CRC?

What are their clinical significances?

Ras/Raf/MEK/ERK: KRAS/NRAS mutations are common and confer EGFR inhibitor resistance. BRAF mutations do not, but are an independent negative risk factor.

PI3K/AKT/mTOR: PI3KCA exon 20 mutations confer EGFR inhibitor resistance. This is worsened with coexisting exon 9 mutation or PTEN loss. Targetable with aspirin?

6

What mutations are associated with pancreatic ductal adenocarcinoma?

All start with a KRAS oncogene hotspot mutation (in PanIN).

Progression through tumor supressor losses of TP53, SMAD4, and CDKN2A.

7

What muations are associated with pancreatic neuroendocrine tumors?

Most involve MEN1 (note MEN syndrome). ATRX/DAXX (telomerase-independent telomere maintenance) is involved in 45%. A minority involve VHL (note VHL syndrome).

8

What mutations are associated with solid-pseudopapillary neoplasms?

Almost all cases have mutations of CTNN1B (beta-catenin). Results in overexpression of cyclin D.

9

What mutations are associated with acinar cell carcinoma?

Very similar profile to PDAC: KRAS, SMAD4, TP53...

10

What mutations are associated with pancreatoblastoma?

Loss of chr 11p (seen sporadically and in Beckwith-Wiedemann)

11

What mutations are associated with IPMNs and MCNs?

KRAS, TP53, SMAD4 in high-grade dysplasia...

IPMNs can harbor GNAS mutations, while MCNs do not.

12

What mutation is associated with serous cystadenoma?

VHL