What is the genetic basis of cancer, specifically in breast cancer?

The Genetic Basis of Cancer and Its Application to Breast Cancer

Cancer fundamentally results from genetic alterations that disrupt normal cellular growth control mechanisms, with breast cancer specifically involving mutations in high-penetrance genes like BRCA1/2, moderate-penetrance genes like CHEK2, ATM, and PALB2, and low-penetrance genetic variants that collectively contribute to disease risk. 1

Fundamental Genetic Mechanisms of Cancer

Cancer develops through the accumulation of genetic alterations that affect key cellular processes:

• DNA Damage and Repair: Mutations in genes responsible for detecting and repairing DNA damage allow genetic errors to accumulate 2
• Cell Cycle Dysregulation: Aberrations in cell cycle checkpoints enable uncontrolled cell division 3
• Apoptosis Evasion: Cancer cells acquire mutations that prevent programmed cell death 3
• Growth Signaling: Mutations in proto-oncogenes and tumor suppressor genes disrupt normal growth control 4

High-Penetrance Breast Cancer Genes

These genes confer the highest risk of breast cancer development:

• BRCA1:

  • 65-82% lifetime breast cancer risk
  • Tumors typically triple-negative with high histologic grade
  • 39-48% lifetime ovarian cancer risk
  • Functions in double-stranded DNA break repair 2, 1

• BRCA2:

  • 45-85% lifetime breast cancer risk
  • Tumors more similar to sporadic breast cancers
  • 11-23% lifetime ovarian cancer risk
  • 5-10% lifetime male breast cancer risk
  • Also involved in DNA repair pathways 2, 1

• Other High-Penetrance Genes:

  • TP53: Associated with Li-Fraumeni syndrome
  • PTEN: Associated with Cowden syndrome
  • CDH1: Associated with hereditary diffuse gastric cancer
  • STK11: Associated with Peutz-Jeghers syndrome 2

Moderate-Penetrance Breast Cancer Genes

These genes confer approximately a twofold increase in breast cancer risk:

• CHEK2:

  • Protein kinase involved in cell cycle regulation at G2
  • CHEK2*1100delC mutation confers RR 1.70 for females, RR 10.3 for males
  • Stabilizes p53 and interacts with BRCA1 2

• BRIP1 (BACH1):

  • Interacts with BRCA1 C-Terminus domain
  • RR 2.0 for all women, RR 3.5 for women under 50
  • Biallelic mutations cause Fanconi anemia type J 2

• ATM:

  • Protein kinase involved in DNA damage monitoring and repair
  • RR 2.37 for breast cancer
  • Biallelic mutations cause ataxia-telangiectasia 2

• PALB2:

  • Associates with BRCA2, involved in nuclear localization
  • RR 2.3 for all women, RR 3.0 for women under 50
  • Biallelic mutations cause Fanconi anemia type N 2

Low-Penetrance Genetic Variants

• Single-nucleotide polymorphisms (SNPs) distributed across the genome contribute to breast cancer risk in a polygenic fashion
• Individual variants confer small risk increases but may have cumulative effects
• Genome-wide association studies have identified numerous risk loci 2

Clinical Application of Genetic Knowledge in Breast Cancer

Risk Assessment and Genetic Testing

• Testing recommended for individuals with:
  • Three or more breast/ovarian cancer cases (at least one <50 years)
  • Two breast cancer cases <40 years
  • Male breast cancer and ovarian/early-onset female breast cancer 1

Management of High-Risk Individuals

• Enhanced Surveillance:

  • Begin at ages 25-30
  • Monthly self-examinations
  • Clinical breast examinations twice yearly
  • Annual mammography and MRI 1

• Risk-Reducing Interventions:

  • Prophylactic mastectomy reduces breast cancer risk by >90%
  • Risk-reducing salpingo-oophorectomy reduces ovarian cancer risk by 80-90% 2
  • Chemoprevention with tamoxifen may reduce contralateral breast cancer risk in BRCA mutation carriers 2

Treatment Implications

• BRCA-Associated Tumors:

  • Particularly sensitive to PARP inhibitors due to synthetic lethality
  • Triple-negative phenotype common in BRCA1 carriers affects treatment approach 2, 5

• Molecular Subtyping:

  • Breast cancer treatment is guided by molecular subtypes (hormone receptor-positive/ERBB2-negative, ERBB2-positive, triple-negative)
  • Genetic information helps determine appropriate targeted therapies 6

Clinical Pitfalls and Considerations

1. Variant Interpretation: Not all genetic variants are pathogenic; careful interpretation is required

2. Risk Modification: Environmental factors may modify genetic risk, particularly for moderate-penetrance genes 2

3. Testing Limitations: Multigene panel tests vary in coverage; understanding which genes were tested is crucial 2

4. Evolving Knowledge: Risk estimates continue to be refined as more data becomes available 1

5. Male Breast Cancer Risk: Often overlooked but significant, especially in BRCA2 carriers 2, 1

The genetic basis of breast cancer represents a complex interplay of high-penetrance genes, moderate-penetrance genes, and low-penetrance variants, with implications for risk assessment, prevention, and treatment strategies.