1. Familial adenomatous polyposis
Best Practice Guidelines

2. Contribution of familial cancer syndromes to colorectal cancer
Lynch: Cancer:100, No1,2004

3. Familial adenomatous polyposis - FAP
Thousands of polyps in colon
Certain to become malignant by fourth decade
Prevention of cancer depends on regular sigmoidoscopy
Molecular testing can be used to indicate those requiring clinical screening

4. Extra colonic manifestations in FAP
Upper GI adenomas
Congenital hypertrophy of the retinal pigment epithelium
Desmoid tumour
Osteomas
Epidermoid cysts

5. APC gene associated with FAP

6. Nature of APC mutations
Hundreds identified
Mutations are nonsense, small deletions or insertions (~80%)
Large deletions (7-12%)
“All” mutations lead to a truncated protein product and hence identifiable as pathogenic
Pick up rate for mutations is > 90%

7. Distribution of APC mutations

8. Specific mutations
5bp deletions at codons 1308 and 1061 account for ~5% of cases
Attenuated disease associated with 5’ and 3’ mutations and also with mutations in exon 9
p.Ile1307Lys mutation found in approximately 6% of the Ashkenazi Jewish population and has been associated with increased risk of colon cancer
Predictive testing not recommended
p.Glu1317Gln – probably not now associated with colon cancer

10. FAP- summary Clinically identifiable condition
Caused by mutations in one gene
Effect of mutations is clear
High pick up rate for mutations
Effective clinical screening test for those at high risk
Some evidence of genotype-phenotype correlations though of little value clinically

11. BP Guidelines Mutation analysis
MLPA for deletions/duplications
Either mutation scanning approach or direct sequencing
PTT for exon 15?
~66% of mutations
Linked markers
Intragenic and flanking markers available
When should these be used?
Cytogenetics?

12. BP Guidelines Reporting
Identification of a clearly pathogenic mutation
Confirms a diagnosis of FAP
Offer presymptomatic testing to relatives
At what age?

13. BP Guidelines Reporting
No mutation identified
Need to describe sensitivity of testing carried out
Cannot completely rule out FAP
Offer linkage if clinical diagnosis is sufficiently sound

14. BP Guidelines Reporting
Identification of p.Ile1307Lys/p.Glu 1317Gln
“(this patient) was found to carry the APC p.Ile1307Lys/p.Glu1317Gln variant. No other variants were detected. This variant was formerly considered a predisposition allele for colorectal cancer, however, more
recent papers [cite ref(s)] indicate that there is no statistically or clinically significant association between carrying the variant and increased risk of colorectal cancer. Detection of this variant does not confirm a diagnosis of FAP and predictive testing for this variant is not indicated in (this patient’s) relatives.”

15. BP Guidelines Reporting
Other missense variant or synonymous change
Ensure that change does not affect splicing
Report according to BP unclassified variant guidelines
Are these relevant at all as all known mutations causing FAP are truncating?

16. BP Guidelines Reporting
Presymptomatic testing
If mutation present patient is highly likely to develop FAP
APC mutations are “100%” penetrant
If absent won’t develop FAP and is a population risk of colon cancer

17. Prenatal testing
Is there a role for it?
Prenatal
PGD?