What are the familial colon cancer diseases?

Familial Colon Cancer Diseases

The main familial colon cancer diseases are intestinal polyposis syndromes (including familial adenomatous polyposis, juvenile polyposis, and Peutz-Jeghers polyposis) and hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome), which together account for approximately 5-8% of all colorectal cancers. 1

Classification of Familial Colorectal Cancer Syndromes

1. Intestinal Polyposis Syndromes

Familial Adenomatous Polyposis (FAP)

• Genetic basis: Autosomal dominant mutation in the APC gene on chromosome 5q21-22 1
• Clinical features:
  • Characterized by ≥100 adenomatous polyps in colon and rectum 1
  • Nearly 100% lifetime risk of colorectal cancer if untreated 1
  • Average age of adenoma appearance: 16 years 1
  • Average age of colorectal cancer development: 39 years 1
  • Accounts for <1% of all colorectal cancers 2
• Variants:
  • Attenuated FAP (AAPC): Fewer polyps, later onset
  • Turcot syndrome: FAP with brain tumors (medulloblastoma) 1
• Extra-intestinal manifestations: Epidermoid cysts, osteomas of jaws, desmoid tumors, gastric fundic gland polyps, congenital hypertrophy of retinal epithelium, thyroid carcinoma, hepatoblastoma 1, 3

MUTYH-Associated Polyposis (MAP)

• Genetic basis: Autosomal recessive mutation in the MYH gene on chromosome 1p 1
• Clinical features:
  • FAP-like presentation but with recessive inheritance pattern
  • Often explains FAP cases without detectable APC mutation 1

Juvenile Polyposis (JP)

• Genetic basis: Mutations in SMAD4/18q or BMPR1A/10q genes 1
• Clinical features:
  • Multiple hamartomatous polyps in colon, stomach, and small intestine
  • Approximately 50% lifetime cancer risk 1
  • Polyps are hamartomatous with hyperplastic stroma and inflammation 1

Peutz-Jeghers Polyposis (P-JP)

• Genetic basis: Mutation in LKB1/19p gene 1
• Clinical features:
  • Hamartomatous polyps throughout GI tract
  • Approximately 10% lifetime colorectal cancer risk 1
  • Characteristic mucocutaneous pigmentation 2
  • Risk for other cancers including breast, pancreas, and gynecologic malignancies

2. Hereditary Non-Polyposis Colorectal Cancer (HNPCC/Lynch Syndrome)

• Genetic basis: Autosomal dominant mutations in DNA mismatch repair genes:
  • MLH1 (chromosome 3p)
  • MSH2 (chromosome 2p)
  • MSH6 (chromosome 2p)
  • PMS2, PMS1, MLH3 (less common) 1
• Clinical features:
  • Accounts for approximately 3-5% of all colorectal cancers 2, 3
  • 80% lifetime risk of colorectal cancer 1
  • Early age of onset (average 45 years)
  • Predilection for proximal colon
  • Accelerated adenoma-carcinoma sequence 1
  • Microsatellite instability (MSI) in tumors 2
• Extra-colonic cancers: Endometrial, ovarian, gastric, urinary tract, small bowel, hepatobiliary, pancreatic, brain (Turcot variant), sebaceous tumors (Muir-Torre variant), breast, and prostate 3

3. Other Familial Colorectal Cancer Syndromes

Cowden Syndrome/PTEN Hamartoma Tumor Syndrome

• Genetic basis: PTEN gene mutation 1
• Clinical features: Multiple hamartomas, increased risk of breast, thyroid, and endometrial cancers

Serrated Polyposis Syndrome

• Genetic basis: Not clearly identified 1
• Clinical features: Multiple serrated polyps throughout the colon with increased CRC risk

Clinical Management

Genetic Testing and Surveillance

1. FAP:

   • Annual sigmoidoscopy beginning at age 10-12 years for at-risk individuals 1
   • Genetic testing should be considered for patients with FAP who have relatives at risk 1
   • Prophylactic colectomy typically at age 20-25 years 1
   • Options include colectomy with ileorectal anastomosis (requires lifelong rectal surveillance) or proctocolectomy with ileal pouch-anal anastomosis 1
   • Periodic duodenoscopy for duodenal cancer surveillance 1

2. HNPCC/Lynch Syndrome:

   • Colonoscopy beginning at age 20-25 years
   • Every 1-2 years through age 40, then annually thereafter 3
   • Surveillance for extracolonic cancers as appropriate

3. Common Familial Risk (non-syndromic):

   • One first-degree relative with CRC: 2-3 fold increased risk
   • Two first-degree relatives with CRC: 3-4 fold increased risk
   • First-degree relative with CRC diagnosed before age 50: 3-4 fold increased risk 1
   • One first-degree relative with adenomatous polyp: ~2 fold increased risk 1

Molecular Characteristics

Hereditary colorectal cancers can be divided into two main molecular pathways:

1. Microsatellite Instability (MSI) Pathway:

   • Characteristic of Lynch syndrome
   • Right-sided predominance
   • Diploid DNA
   • Indolent behavior
   • Mutations in TGF-β receptor II and BAX genes 2

2. Chromosomal Instability (CIN) Pathway:

   • Characteristic of FAP
   • Left-sided predominance
   • Aneuploid DNA
   • More aggressive behavior
   • Mutations in K-ras, APC, and p53 genes 2

Important Clinical Considerations

• Early identification of hereditary syndromes is critical for cancer prevention through appropriate surveillance and prophylactic interventions 1
• A detailed family history of cancer at all anatomical sites is essential for diagnosis 2
• Approximately 20-30% of all colorectal cancers show familial clustering, suggesting genetic factors beyond the well-defined syndromes 1, 4
• Multigene panel testing may be appropriate when clinical features overlap multiple syndromes 1
• The risk of colorectal cancer in family members correlates with the age of diagnosis in affected relatives, with younger age at diagnosis conferring higher risk 1

Early recognition and appropriate management of these hereditary syndromes significantly improve survival outcomes and quality of life for affected individuals 1.