Genetics · MU Sofia

48. Hereditary cancer syndromes - general characteristics. Syndromes with genetic predisposition to colorectal carcinoma: familial adenomatous polyposis (FAP); hereditary nonpolyposis colon cancer (HNPCC); Cowden syndrome.

Covers the general features of hereditary cancer syndromes, including the two-hit model and the genes involved, then takes familial adenomatous polyposis, HNPCC (Lynch syndrome) and Cowden syndrome in turn. For each it gives the gene and chromosome, the normal protein function, the pathogenesis steps, clinical features, diagnosis and management, with extracolonic manifestations and associated cancers listed separately. The note also mentions Gardner syndrome as a variant of FAP.

Inside: 10 sections · 7 labelled pictures · 16 flashcards · 5 min

Topic 48 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 10 sections, about 619 words (5 min of reading), with 16 flashcards.

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  1. Hereditary cancer syndromes - general characteristics. Syndromes with genetic predisposition to colorectal carcinoma: familial adenomatous polyposis (FAP); hereditary nonpolyposis colon cancer (HNPCC); Cowden syndrome.
  2. I. GENERAL CHARACTERISTICS OF HEREDITARY CANCER SYNDROMES
  3. II. FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
  4. III. HEREDITARY NONPOLYPOSIS COLORECTAL CANCER (HNPCC / LYNCH SYNDROME)
  5. IV. COWDEN SYNDROME (PTEN HAMARTOMA TUMOR SYNDROME)
  6. Normal Function of PTEN
  7. Pathogenesis of Cowden Syndrome
  8. Clinical Features
  9. Diagnosis
  10. Management

I. GENERAL CHARACTERISTICS OF HEREDITARY CANCER SYNDROMES

Hereditary cancer syndromes are disorders caused by germline mutations in genes that regulate:

  • cell cycle control,
  • DNA repair,
  • apoptosis,
  • genomic stability.

Individuals inherit a genetic predisposition to cancer, not cancer itself. Malignancy develops after accumulation of additional somatic mutations.

Key General Features

Hereditary cancer syndromes are characterized by:

  • early age of cancer onset,
  • multiple primary tumors in the same individual,
  • family clustering of specific cancers,
  • autosomal dominant inheritance in most cases,
  • involvement of tumor suppressor genes or DNA repair genes.

General Pathogenesis

  1. 1. Germline mutation represents the first hit (present in all cells).
  2. 2. A somatic mutation provides the second hit (Knudson hypothesis).
  3. 3. Loss of tumor suppressor or DNA repair function.
  4. 4. Accumulation of additional driver mutations.
  5. 5. Development of malignancy in target tissues.

Genes Commonly Involved

  • Tumor suppressor genes (APC, PTEN)
  • DNA repair genes (MLH1, MSH2, MSH6, PMS2)

II. FAMILIAL ADENOMATOUS POLYPOSIS (FAP)

Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary cancer syndrome characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, with an almost 100% risk of colorectal cancer if untreated.

Genetic Basis

  • Gene: APC
  • Chromosome: 5q21
  • Function: Tumor suppressor involved in Wnt/β-catenin signaling pathway

Normal Function of APC

The APC protein regulates β-catenin degradation, preventing excessive transcription of genes promoting cell proliferation. Loss of APC leads to unchecked epithelial cell proliferation in the intestinal mucosa.

Pathogenesis of FAP

  1. 1. Germline mutation in one APC allele.
  2. 2. Second somatic hit in intestinal epithelial cells.
  3. 3. Accumulation of β-catenin in nucleus.
  4. 4. Activation of proliferation-related genes.
  5. 5. Formation of numerous adenomatous polyps.
  6. 6. Progressive malignant transformation.

Clinical Features

  • Onset of polyps in childhood or adolescence
  • Hundreds to thousands of colorectal adenomas
  • Colorectal cancer often before age 40 if untreated

Extracolonic Manifestations

  • Duodenal and gastric polyps
  • Desmoid tumors
  • Osteomas of skull and mandible
  • Congenital hypertrophy of retinal pigment epithelium (CHRPE)

Gardner syndrome is a variant of FAP with prominent extracolonic features.

Diagnosis

  • Colonoscopy showing numerous adenomas
  • Genetic testing for APC mutation

Management

  • Prophylactic colectomy
  • Lifelong surveillance for extracolonic cancers
  • Genetic counseling and family screening

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