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Familial adenomatous polyposis

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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?

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