Colorectal! Flashcards
What proteins does APC normally bind with?
B-catenin, axin, GSK3
Genes transcribed when Wnt pathway activated?
C-MYC, cyclin D1.
Genes hypermethylated in CRC?
APC, E-cadherin, MMR
CIMP phenotype?
CpG island methylator phenotype. Frequent hypermethylation, little mutation. Not adenoma-carcinoma chromosomal instability progression. High MSI and BRAF/KRas mutations. Lack hallmark mutations in APC, 18q, TP53. Usually have MLH1 promoters hypermethylated hence MSI.
Is RAS normally membrane bound?
Yes, by prenylation.
Which exon normally effected in Ras mutations?
Exon 2; old assay just looked for this.
TGF-B binding?
TGF-B inhibits proliferation. Binds to RII; RI transduces, SMAD2 phosphorylated then interacts with SMAD4 leading to increased differentiation and decreased proliferation
Percentage of CRC taken up by FAP and HNPCC?
1% and 5% respectively!
Amsterdam criteria?
3 relatives with cancer, 2 successive generations, 1 under 50
Diagnosing HNPCC?
Combined Bethesda MSI PCR at 5 key loci then IHC of MMR genes. If positive, sequence MMR genes to see i have germline mutation.
Two ways that same pathway can be affected by the two different pathways in CRC?
- In mutator (MSI), often get slippage of TGB-B receptor (RII) leading to truncated form and so cannot bind.
- In classic adenoma-carcinoma chromosomal instability, get deletions on long arm of chromosome 18 that delete SMAD4 (downstream).
OC vs CTC?
- CTC. No bowel prep, cheaper, no sedation. Risk of perforation 1/1000; risk of death 1/10000
- OC. No radiation to young, slightly better sensitivity, can biopsy.
Chemotherapy regime used in CRC?
FOLFOX i.e. 5-fluorouracil (fluoropyrimidine antimetabolite) and oxaliplatin (and folinic acid).
Bevacizumab?
Used in metastatic CRC. Lots of them overexpress VEGFR (associated with increased stage and poorer prognosis). Binds to VEGF.
Role of EGFR therapy in CRC?
- Cetuximab in adjuvant setting; look for KRAS WT first and Raf mutations too. Licensed with chemotherapy in firstline, secondline and later for mCRC.
High MSI and chemo?
Worse response to 5FU; better to irinotecan.
Ramucirumab in CRC?
Anti-EGFR. Approved in combination with FOLFORI in mCRC (folinic acid, 5-fluoruracil, irinotecan) after failure of bevacizumab and chemotherapy.
Who gets adjuvant therapy in CRC?
Not Dukes A; Dukes B1 if +ve margins; all others too.
Poor prognostic markers in early and late CRC?
Early = high MSI, dMMR. Late = BRAF mutant.
Potential factors include KRAS, EGFR overexpression, 18qLOH, SMAD4 loss.
Follow up post CRC surgery?
Clinic in 4-6 weeks; 2 CTs C/A/P in first 3 years; CEA at least six monthly; surveillance OC at 1 and 5 years.
Role of adjuvant therapy?
Reduces local and systemic recurrence
What % of CRC is incurable at Px?
20%
How do we know that APC mutations can be dominant negative?
Some FAP patients will be heterozygous. Same applies to BRCA.
