Colorectal - FAP Flashcards
Provide a brief breakdown of the causes of colorectal cancer
~85% sporadic vs. ~15% = established familial genetic syndrome:
- Lynch syndrome (3-5%)
- FAP, PJS, PTEN (<1%)
- Unspecified familial cancer (~10%)
What is FAP?
Familial adenomatous polyposis.
What gene is associated with FAP?
APC gene.
What is the MoI for FAP?
Autosomal dominant
What proportion of FAP cases are de novo?
10%
What is FAP characterised by?
Development of 100s to 1000s of adenomatous colonic polyps during 2nd decade of life (range 7-36yrs).
By 35yrs, 95% of cases have polyps.
Children/adolescents tend to be asymptomatic until the adenomas cause rectal bleeding or anaemia.
Non-specific symptoms = change in bowel habits, abdo pain, weight loss.
Does FAP develop into CRC?
Yes - almost 100% risk if patient doesn’t have early-stage colectomy.
CRCs tend to develop approx 10yrs after the polyps appear.
Colectomy advised when >20-30 adenomas/multiples adenomas with advanced histology have occurred.
With current screening procedures, majority of patients are diagnosed before the development of CRC.
What does FAP screening involve?
Colonoscopy screening from 10-12yrs for individuals with FAP/APC mut, or those at risk of FAP but with no genetic testing - annual colonoscopy once polyps detected until colectomy.
With current screening procedures, majority of patients are diagnosed before the development of CRC.
What is attenuated FAP?
Milder, later onset form of FAP - patients develop fewer adenomas (0-100).
Associated with particular APC mutations (e.g. C-terminal non-NMD truncated proteins).
Similar phenotype may be due to muts in other genes (e.g. MUTYH).
What is the mechanism/pathway by which APC has an effect?
Part of the Wnt signalling pathway.
In absence of Wnt signal/presence of wildtype APC, B catenin is degraded.
In the absence of APC/presence of Wnt, mutant APC can’t bind B-catenin so it accumulates and activates downstream TFs resulting in target gene expression. These genes (e.g. c-myc) change the proliferation and differentiation state of cells.
Is APC/FAP a good example go a genotype/phenotype correlation?
Yes.
Mutations causing FAP/AFAP are nearly always null/truncating. Missense mutations confer small increased risk of polyps.
Mutations in mutation cluster region develop highest number of polyps + highest risk of CRC at a young age.
AFAP can arise through nonsense mutations in large C-terminal final exon - don’t undergo NMD = partially functioning proteins.
How is FAP tested for?
Diagnosis based on Fhx and clinical phenotype followed by genetic confirmation.
Included as part of CRC panel testing.
Important to be able to detect partial/whole gene dels as seen in ~10% of APC-associated cases.
Why is there a lower mutation detection rate in simplex cases (single occurrence in a family) compared to persons with an affected parent?
Due to somatic mosaicism.
Seq of APC in DNA from peripheral blood lymphocytes may fail to detect the causative variant due to weak mutation signals.
Is FAP typically associated with pre-symptomatic testing in minors at risk?
Yes - colon screening for those at risk of classic FAP begins as early as 10-12yrs so usually offer genetic testing by aged 10yrs.
This is one of the few conditions where pre symptomatic testing in children is approved (others = NF2 and VHL).
Are there any treatments available for FAP?
Safest = surgical resection of the colon when polyposis develops.
Chemoprevention - can delay development of adenomas in upper/lower GI tract, thereby delaying prophylactic colectomy. Can also prevent recurrence of adenomas in retained rectum post-prophylactic surgery.
