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Familial Adenomatous
Polyposis• 1 in 10,000 incidence
• 100’s to 1000’s of colonic adenomas by teens
– Cancer risk: colon, gastric, duodenum (periampulla), small bowel, pancreas, papillary thyroid, childhood hepatoblastoma
• 7% risk of CRC by 21 yrs; 93% by 50 yrs
• Autosomal dominant: APC gene mutations
• Variants: Gardner (extracolonic), Turcot(medulloblastoma)
Rectal zone Sigmoid colon
“apple core” lesion of distal sigmoid: www.medlib.med.utah.edu/WebPathwww.medlib.med.utah.edu/WebPath
Inherited PolyposesFAP/Gardners
• Associated with mutation of the adenomatouspolyposis coli (APC) gene on chromosome 5 -encodes tumor suppressor gene
• Polyps appear usually in the second or third decade; malignant changes have occurred as young as 9 years of age
• Polyps are typically small and sessile; endoscopic resection difficult because of huge numbers
Inherited PolyposesFAP/Gardners
• Association with osteomas (skull), desmoids (intra-abdominal), or epidermoid cysts, along with small bowel tumors (those in duodenum have high malignant potential) : Gardners
• Association with medulloblastoma or glioblastoma : Turcots
• Each of the above shares the genetic defect with FAP.
Polyps and tumors
• Colon: Adenomas, less than 1 cm, multiple, numbers may correlatewith site of mutation
• Gastric: – Fundic retention polyps - - no malignant potential– Adenomatous polyps – probably malignant potential – but no
increased gastric Ca risk• Duodenum – clustered around papilla – found in 33-92% FAP
patients– Spigelman staging – suggests therapy
• Desmoids– Not malignant but may be nasty– Usually in mesentery, also abdominal wall and extremities– Occur in 10% - cause of death in 1%
Other FAP stuff
• Osteomas - usually mandible• Epidermoid, sebaceous cysts• Fibromas, lipomas• CHRPE – retinal lesions asymptomatic – correlates with
mutation
Natural History
Adenomas begin to develop in early adolescence
100-5000 colorectal adenomas
Cancer risk increases with number of adenomas
If untreated100% colorectal cancer risk
Median life expectancy – 42 years
FAP – surveillance
• Colon– Annual sigmoidoscopy, age 10-12 yrs– Prophylactic colectomy following polyp detection
w/continued surveillance of rectum, ileal pouch• Duodenal/gastric
– EGD age 25, repeat 1-3 yrs• Thyroid
– Annual PE, age 10• Hepatoblastoma
– Annual screen by abd U/S & AFP from birth to 5 yrs.
Gastroenterology 2001; 121: 195. AGA Statement
Inherited PolyposesFAP/Gardners
• Affected proband should have genetic testing -disease is inherited in autosomal dominant fashion
• If defect is identified in proband, family members can also be screened to identify those at risk
• Otherwise, children should begin screening with annual flexible sigmoidoscopy by age 10-13
• Dx: > 100 POLYPS• Surgery: > 5 mm, > 6-9 per cm2 . Timing in others is
controversial; post op need screening EGD’s
Genetic Testing: FAP/AFAP
• Test an affected family member first!
– After genetic counseling and informed consent
• APC gene testing can confirm a suspected diagnosis
• Family members of a person with a known APC mutation can have mutation-specific testing
• Genetic testing for children at risk for FAP can be considered before beginning colon screening
Inherited PolyposesFAP/Gardners
• Sulindac:– In a variety of animal studies, NSAIDs have been
shown to decrease tumor growth– In early human FAP trials, sulindac caused tumor
regression.– This effect replicated in subsequent randomized,
placebo controlled, double-blinded trials– Problems:
• Tumors recur when drug stopped• Side effects limit utility; specific COX 2 inhibitors
needed
Attenuated FAP
• 20 to 100 polyps, usually more proximal– Onset later than FAP, average AOO = 50
– Lifetime risk of CRC = 80%
• Extracolonic tumors occur at same rate as FAP
• Variant of FAP, mutations in same APC gene
• Surveillance: – annual colonoscopy starting late teens or early 20’s
– Option of subtotal colectomy
APC gene mutation in Ashkenazi Jews
• Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)
• Found in 6% of the general AJ population
– 12% of AJs with CRC
– 29% of AJs with CRC and a positive family history
• Lifetime risk of CRC in mutation carrier is 10-20%
• Screening: colonscopy every 2-5 yrs starting at 35 yrs
MAP syndrome/MYH gene
• Multiple adenomatous polyposis (MAP) syndrome– Autosomal recessive; mutations in the MYH gene
– Median number of polyps = 55
– Mean age of polyp diagnosis = 30-50 years
– Polyps mainly small, mildly dysplastic tubular adenomas. Some tubulovillous, hyperplastic, serrated adenomas, microadenomas
• 30% of individuals with 15-100 polyps have homozygous mutations in the MYH gene
• Genetic testing should be offered if >15 polyps (and APC gene testing negative)
Peutz-Jeghers syndrome
• <1% of all CRC cases• Hamartomatous polyps of GI tract as early
as 1st decade• Mucocutaneous hyperpigmentation
– lips, mouth, buccal mucosa, fingers – Usually seen in children < 5 yrs
• Cancer risk: – colon, small intestine, stomach, pancreas,
breast, ovaries, uterus, testes, lungs, kidneys• Mutations in STK11 gene
– found in 70% of familial cases and 30-70% of sporadic cases
Inherited PolyposesPeutz-Jeghers
• Hamartomatous polyps associated with mucocutaneous pigmentation.
• Brown-black freckles involving lips, oral mucosa and other sites - may fade with age
• Polyps, 1-3 cm in size, involve jejunum, colon, stomach and duodenum
• Sx: abdominal pain (intussusception), anemia• Risk of Ca (18 fold increase) of
duodenum/stomach, small bowel, and ovary
Inherited PolyposesPeutz-Jeghers
• Fundic or duodenal polyps should be removed promptly because of malignant potential
• Female patients should have periodic pevic examinations
• Genetic lesion: serine/threonine kinase, located 19p13.3 (most families)
Familial Juvenile Polyposis
• <1% of all CRC cases
• Autosomal dominant
• 5 or more juvenile polyps in colon or GI tract – Appear in 1st or 2nd decade
– 50% lifetime risk of CRC; AOO in 30’s
– Increased risk gastric, GI, pancreatic CA
• ~50% of cases have mutations in either the MADH4 or BMPR1A genes
Inherited PolyposesJuvenile polyposis
• Defined as the presence of 5 or more juvenile polyps within the colon
• Usually diagnosed within the first decade of life: typically presents with bloody stools
• May present with rectal prolapse or intussusception
• Genetically heterogenous• Three fold increase in risk of colorectal cancer:
screen with colonoscopy every two years
Inherited PolyposesCowden’s disease
• Hamartomatous polyps throughout the GI tract; most common in the colon and stomach
• Mucocutaneous lesions include hyperkeratoticpapillomas of lips, tongue and nares
• 30% incidence of breast Ca in females; also risk of thyroid tumors
• Lesion on chromosome 10q22-23 - tumor suppressor gene PTEN encoding a dual specificity phosphatase
www.genetests.org
PRINCIPAL INVESTIGATOR: Roberta A Pagon, MD
SPONSORING INSTITUTIONUniversity of WashingtonSeattle, WA
FUNDED BYNational Institutes of HealthContract No. N01-LM-3503
Sequencing ofentire coding region
Mutationscanning
Proteintruncation
testing
Prenataldiagnosis
Clinical confirmation of mutations identified in a
research lab