Colon Cancer Syndromes (Hereditary)

Familial Adenomatous Polyposis (FAP)

< 1% of all cases of colon ca are 2/2 FAP
Autosomal dominant inheritance
Hundreds to thousands of adenomatous polyps, which develop in the teenage years and then progress to cancer between age 30 and 50
most often due to a germline mutation in the APC gene (5q21-q22), less commonly due to a biallelic mutation of the MYH gene (recessive pattern of transmission)
Mutations are detectable in 70% of patients (commercial testing available for APC and MYH)
Approx 95% of persons who meet the clinical criteria for a diagnosis of FAP will have an identifiable mutation in their APC gene
Approx 66% of those that have FAP have inherited a changed APC gene from a parent, whereas 33% are the first person in a family to have FAP
Most common location of cancer is in the periampullary region of the duodenum (b/c of this screening involves both colo and EGD)
Extracolonic manifestations include: benign (desmoids tumors, epidermoid and sebaceous cysts, gastic polys, mandibular osteomas, supernumerary teeth, congenital hypertrophy of the retinal pignement epithelium) and premalignant/malignant (small bowel adenomas and cancer, thyroid ca, gastric ca, CNS tumors, biliary ca)

Attenuated FAP

10 to 100 polyps develop and the polyps and cancer occur about 10 yrs later than classic FAP
Similar gene mutations as FAP
Extracolonic manifestations can occur (as in FAP) if both APC and MYH genes affected

Hereditary Nonpolyposis Colorectal Ca (HNPCC)

Also known as Lynch syndrome
Autosomal dominant syndrome involving mismatch repair genes MLH1 and MLH2
Accelerated adenomaàcarcinoma sequence
80% lifetime risk of colon ca, but generally develops after age 50
Associated with fewer than 10 polyps, cancers tend to occur on the R side of the colon with a mucinous pathology
Diagnosis is based on the Amsterdam II criteria (3-2-1 rule:3 relatives w associated cancer, 2 gnerations affected and 1 person diagnosed before age 50) or the Modified Bethesda Guidelines;
Extracolonic cancers: 40-60% lifetime risk of uterine ca and 10-12% risk of ovarian ca (also associated w cancers of the small bowel, stomach, pancreas and kidney/ureter)

Peutz-Jeghers Syndrome

Rare, autosomal dominant condition with polyps in the small bowel and colon; usually hamartomas, although can undergo malignant transformation (80x increased risk for colon ca)
Germline mutation in STK11 gene
Classic perioral pigmentation
Extracolonic tumors include breast, pancreas, ovaries and lung

Juvenile Polyposis

Autosomal dominant condition with hamartomatous polyps, usually in the distal colon
Congenital manifestations of the GI tract, genitourinary system and hear
Germline mutation in the SMAD4 gene
Lifetime risk of colon ca is approx 70%

(Victoria Kelly MD, 8/31/10)