Presentation on theme: "Familial adenomatous polyposis"— Presentation transcript:
1Familial adenomatous polyposis Best Practice Guidelines
2Contribution of familial cancer syndromes to colorectal cancer Lynch: Cancer:100, No1,2004
3Familial adenomatous polyposis - FAP Thousands of polyps in colonCertain to become malignant by fourth decadePrevention of cancer depends on regular sigmoidoscopyMolecular testing can be used to indicate those requiring clinical screening
4Extra colonic manifestations in FAP Upper GI adenomasCongenital hypertrophy of the retinal pigment epitheliumDesmoid tumourOsteomasEpidermoid cysts
6Nature of APC mutations Hundreds identifiedMutations are nonsense, small deletions or insertions (~80%)Large deletions (7-12%)“All” mutations lead to a truncated protein product and hence identifiable as pathogenicPick up rate for mutations is > 90%
8Specific mutations5bp deletions at codons 1308 and 1061 account for ~5% of casesAttenuated disease associated with 5’ and 3’ mutations and also with mutations in exon 9p.Ile1307Lys mutation found in approximately 6% of the Ashkenazi Jewish population and has been associated with increased risk of colon cancerPredictive testing not recommendedp.Glu1317Gln – probably not now associated with colon cancer
10FAP- summary Clinically identifiable condition Caused by mutations in one geneEffect of mutations is clearHigh pick up rate for mutationsEffective clinical screening test for those at high riskSome evidence of genotype-phenotype correlations though of little value clinically
11BP Guidelines Mutation analysis MLPA for deletions/duplicationsEither mutation scanning approach or direct sequencingPTT for exon 15?~66% of mutationsLinked markersIntragenic and flanking markers availableWhen should these be used?Cytogenetics?
12BP Guidelines Reporting Identification of a clearly pathogenic mutationConfirms a diagnosis of FAPOffer presymptomatic testing to relativesAt what age?
13BP Guidelines Reporting No mutation identifiedNeed to describe sensitivity of testing carried outCannot completely rule out FAPOffer linkage if clinical diagnosis is sufficiently sound
14BP 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, morerecent 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.”
15BP Guidelines Reporting Other missense variant or synonymous changeEnsure that change does not affect splicingReport according to BP unclassified variant guidelinesAre these relevant at all as all known mutations causing FAP are truncating?
16BP Guidelines Reporting Presymptomatic testingIf mutation present patient is highly likely to develop FAPAPC mutations are “100%” penetrantIf absent won’t develop FAP and is a population risk of colon cancer
17Prenatal testingIs there a role for it?PrenatalPGD?