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

0

10

20

30

40

50

60

70

80

3 4 5 6 7 8 9 10 11 12 13 14

15.2

15.3

15.4

15.4

Exon

nu

mb

er

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 GuidelinesMutation 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, 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.”

• 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?