Colorectal!

Question 1

What proteins does APC normally bind with?

Answer 1

B-catenin, axin, GSK3

Question 2

Genes transcribed when Wnt pathway activated?

Answer 2

C-MYC, cyclin D1.

Question 3

Genes hypermethylated in CRC?

Answer 3

APC, E-cadherin, MMR

Question 4

CIMP phenotype?

Answer 4

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.

Question 5

Is RAS normally membrane bound?

Answer 5

Yes, by prenylation.

Question 6

Which exon normally effected in Ras mutations?

Answer 6

Exon 2; old assay just looked for this.

Question 7

TGF-B binding?

Answer 7

TGF-B inhibits proliferation. Binds to RII; RI transduces, SMAD2 phosphorylated then interacts with SMAD4 leading to increased differentiation and decreased proliferation

Question 8

Percentage of CRC taken up by FAP and HNPCC?

Answer 8

1% and 5% respectively!

Question 9

Amsterdam criteria?

Answer 9

3 relatives with cancer, 2 successive generations, 1 under 50

Question 10

Diagnosing HNPCC?

Answer 10

Combined Bethesda MSI PCR at 5 key loci then IHC of MMR genes. If positive, sequence MMR genes to see i have germline mutation.

Question 11

Two ways that same pathway can be affected by the two different pathways in CRC?

Answer 11

1. In mutator (MSI), often get slippage of TGB-B receptor (RII) leading to truncated form and so cannot bind.
2. In classic adenoma-carcinoma chromosomal instability, get deletions on long arm of chromosome 18 that delete SMAD4 (downstream).

Question 12

OC vs CTC?

Answer 12

1. CTC. No bowel prep, cheaper, no sedation. Risk of perforation 1/1000; risk of death 1/10000
2. OC. No radiation to young, slightly better sensitivity, can biopsy.

Question 13

Chemotherapy regime used in CRC?

Answer 13

FOLFOX i.e. 5-fluorouracil (fluoropyrimidine antimetabolite) and oxaliplatin (and folinic acid).

Question 14

Bevacizumab?

Answer 14

Used in metastatic CRC. Lots of them overexpress VEGFR (associated with increased stage and poorer prognosis). Binds to VEGF.

Question 15

Role of EGFR therapy in CRC?

Answer 15

1. Cetuximab in adjuvant setting; look for KRAS WT first and Raf mutations too. Licensed with chemotherapy in firstline, secondline and later for mCRC.

Question 16

High MSI and chemo?

Answer 16

Worse response to 5FU; better to irinotecan.

Question 17

Ramucirumab in CRC?

Answer 17

Anti-EGFR. Approved in combination with FOLFORI in mCRC (folinic acid, 5-fluoruracil, irinotecan) after failure of bevacizumab and chemotherapy.

Question 18

Who gets adjuvant therapy in CRC?

Answer 18

Not Dukes A; Dukes B1 if +ve margins; all others too.

Question 19

Poor prognostic markers in early and late CRC?

Answer 19

Early = high MSI, dMMR. Late = BRAF mutant.

Potential factors include KRAS, EGFR overexpression, 18qLOH, SMAD4 loss.

Question 20

Follow up post CRC surgery?

Answer 20

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.

Question 21

Role of adjuvant therapy?

Answer 21

Reduces local and systemic recurrence

Question 22

What % of CRC is incurable at Px?

Answer 22

20%

Question 23

How do we know that APC mutations can be dominant negative?

Answer 23

Some FAP patients will be heterozygous. Same applies to BRCA.