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.
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)
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
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)
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?
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.
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).
What mutations are associated with solid-pseudopapillary neoplasms?
Almost all cases have mutations of CTNN1B (beta-catenin). Results in overexpression of cyclin D.
What mutations are associated with acinar cell carcinoma?
Very similar profile to PDAC: KRAS, SMAD4, TP53...
What mutations are associated with pancreatoblastoma?
Loss of chr 11p (seen sporadically and in Beckwith-Wiedemann)
What mutations are associated with IPMNs and MCNs?
KRAS, TP53, SMAD4 in high-grade dysplasia...
IPMNs can harbor GNAS mutations, while MCNs do not.
What mutation is associated with serous cystadenoma?