Hereditary Breast Cancer & Genetic Testing

Advances in Molecular Genetic Testing

Due to the increasing genetic heterogeneity of cancers, modern genomic technologies now allow massive parallel sequencing of dozens to hundreds of genes in a single molecular analysis. This enables simultaneous detection of mutations across multiple genes associated with breast cancer, including those involved in hereditary forms of the disease and somatic mutations in tumors that affect prognosis and treatment choices.

BRCA1 & BRCA2: High-Risk Genes for Hereditary Breast Cancer

Women with a strong family history of early-onset breast cancer should undergo genetic testing for mutations in BRCA1 and BRCA2. These tumor suppressor genes play a role in DNA repair mechanisms, and harmful mutationsin these genes lead to loss of function, significantly increasing the risk of developing breast and ovarian cancer.

Key Facts About BRCA1 & BRCA2 Mutations

✔ 20-25% of all hereditary breast cancers are due to BRCA mutations
✔ 5-10% of all breast cancer cases are associated with these mutations
✔ 15% of ovarian cancers are linked to BRCA mutations
✔ Men with BRCA mutations have increased risks of breast & prostate cancer
✔ BRCA mutations may also be linked to pancreatic cancer in both sexes

Risk Estimates for Women Carrying BRCA Mutations

• BRCA1 mutation: 55-65% lifetime risk of developing breast cancer
• BRCA2 mutation: ~45% lifetime risk of developing breast cancer
• Risk of ovarian cancer: ~40% for BRCA1 and 10-20% for BRCA2 carriers
• However, only 5-10% of women diagnosed with breast cancer carry BRCA mutations

Who Should Consider Genetic Testing?

International guidelines, such as those from the American Society of Breast Surgeons and National Comprehensive Cancer Network (NCCN), provide criteria for genetic testing.

✔ Individuals with a family history of breast or ovarian cancer at a young age
✔ Multiple cases of breast or ovarian cancer in first-degree relatives
✔ Men with breast cancer
✔ Ashkenazi Jewish ancestry, where certain BRCA mutations are more prevalent
✔ Individuals with personal history of triple-negative breast cancer before age 60

Since BRCA mutations are autosomal dominant with variable penetrance, not all carriers develop cancer, and severity varies.

Beyond BRCA: Other Breast Cancer Susceptibility Genes

For many years, BRCA1 & BRCA2 were the primary focus of genetic testing, but 15-20% of patients with a family history of breast cancer do not carry these mutations.

✔ Other high-risk genes: TP53, PTEN, CDH1, PALB2
✔ Moderate-risk genes: ATM, CHEK2, RAD51C/D
✔ Low-risk genes: Common genetic variants associated with slight risk elevation

Benefits of Genetic Testing

Genetic testing provides valuable insights for patients and their families:

✔ Identification of high-risk individuals for early monitoring
✔ Tailored screening programs for early cancer detection
✔ Guidance on preventive options (e.g., risk-reducing mastectomy, oophorectomy)
✔ Family risk assessment for relatives who may be mutation carriers
✔ Potential targeted therapies (e.g., PARP inhibitors for BRCA-related cancers)

Genetic Counseling & Family Testing

When a pathogenic BRCA mutation is found, close family members (siblings, children, parents) have a 50% chance of inheriting the same mutation. More distant relatives (cousins, aunts, uncles, grandparents) may also carry the mutation, even if they have not been diagnosed with cancer.

💡 Genetic counseling is crucial for individuals with a strong family history or a known mutation to help determine risk-reduction strategies.

Understanding Penetrance & Risk Categories

Cancer risk depends on the gene involved, and mutations are classified based on penetrance:

✔ High penetrance (relative risk >5): BRCA1, BRCA2, TP53, PTEN
✔ Moderate penetrance (risk 1.5–5): CHEK2, ATM, PALB2
✔ Low penetrance (risk <1.5): Common genetic variants

Not all high-risk mutations lead to cancer due to gene-environment interactions and lifestyle factors (diet, exercise, hormonal exposure).

Genetic Testing & Personalized Medicine

Understanding hereditary cancer risks through molecular testing allows for personalized prevention, surveillance, and treatment. Even in the absence of family history, genetic testing may still uncover mutations linked to hereditary or sporadic breast cancer, enabling proactive medical decision-making.