Presentation on theme: "Familial adenomatous polyposis Best Practice Guidelines."— Presentation transcript:
Familial adenomatous polyposis Best Practice Guidelines
Lynch: Cancer:100, No1,2004 Contribution of familial cancer syndromes to colorectal cancer
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
Extra colonic manifestations in FAP Congenital hypertrophy of the retinal pigment epithelium Desmoid tumour Osteomas Epidermoid cysts Upper GI adenomas
APC gene associated with FAP
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%
Distribution of APC mutations
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
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
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?
BP Guidelines Reporting Identification of a clearly pathogenic mutation Confirms a diagnosis of FAP Offer presymptomatic testing to relatives At what age?
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
BP Guidelines Reporting “(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.” Identification of p.Ile1307Lys/p.Glu 1317Gln
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?
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
Prenatal testing Is there a role for it? Prenatal PGD?