Genetics · MU Sofia

49. Hereditary cancer syndromes - general characteristics. Hereditary breast and ovarian cancer.

Explains hereditary breast and ovarian cancer as an autosomal dominant syndrome linked to BRCA1 and BRCA2, covering the genes and their DNA repair role, the stepwise pathogenesis, and lifetime cancer risks in a table. It then reviews clinical features, family history, inheritance with incomplete penetrance, who should be tested, surveillance, risk-reducing surgery, PARP inhibitor therapy and genetic counselling.

Inside: 2 sections · 5 labelled pictures · 2 tables · 14 flashcards · 2 min

Topic 49 of 65 in the MU Sofia syllabus for Genetics (Medicine, Year 3). The free AceMed note covers it in 2 sections, about 311 words (2 min of reading), with 14 flashcards.

In this note

  1. Hereditary cancer syndromes - general characteristics. Hereditary breast and ovarian cancer.
  2. I. HEREDITARY BREAST AND OVARIAN CANCER (HBOC)

I. HEREDITARY BREAST AND OVARIAN CANCER (HBOC)

Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant hereditary cancer syndrome characterized by a markedly increased risk of:

  • breast cancer,
  • ovarian cancer,
  • and, to a lesser extent, other malignancies.

Genetic Basis

Both genes encode proteins essential for homologous recombination, a high-fidelity DNA repair pathway.

Normal Function of BRCA1 and BRCA2

BRCA1 and BRCA2 maintain genomic stability by repairing DNA double-strand breaks through homologous recombination. They also participate in cell cycle checkpoint control and help prevent propagation of genetically damaged cells.

Loss of BRCA function leads to error-prone DNA repair, resulting in accumulation of chromosomal aberrations and oncogenic mutations.

Pathogenesis of HBOC

  1. 1. Germline mutation in one BRCA allele (first hit).
  2. 2. Somatic loss or inactivation of the second allele in breast/ovarian epithelial cells.
  3. 3. Defective homologous recombination repair.
  4. 4. Increased chromosomal instability.
  5. 5. Accumulation of driver mutations.
  6. 6. Malignant transformation of epithelial cells.

Cancer Risks Associated with HBOC

Clinical Features Suggestive of HBOC

Breast Cancer

  • Early onset (often <50 years)
  • Bilateral breast cancer
  • Triple-negative breast cancer (especially BRCA1)

Ovarian Cancer

  • Usually high-grade serous carcinoma
  • Often diagnosed at advanced stage

Family History

  • Multiple affected relatives
  • Breast and ovarian cancer in same family
  • Male breast cancer

Inheritance Pattern

  • Autosomal dominant with incomplete penetrance
  • Both males and females can be carriers
  • Cancer risk differs by sex and gene involved

Diagnosis

Who Should Be Tested

  • Individuals with strong family history
  • Early-onset breast cancer
  • Ovarian cancer at any age
  • Male breast cancer
  • Known familial BRCA mutation

Diagnostic Methods

  • Germline genetic testing (BRCA1/BRCA2 sequencing)
  • Tumor testing may guide targeted therapy

Management and Prevention

Surveillance

  • Early and intensive screening
  • Breast MRI and mammography
  • Transvaginal ultrasound and CA-125 (limited sensitivity)

Risk-Reducing Surgery

  • Prophylactic bilateral mastectomy
  • Prophylactic salpingo-oophorectomy (significantly reduces ovarian cancer risk)

Targeted Therapy

  • PARP inhibitors (synthetic lethality in BRCA-deficient tumors)

Genetic Counseling

  • Essential for patients and relatives
  • Includes:
  • risk assessment,
  • testing strategy,
  • reproductive options,
  • psychological support.

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