Genetic Factors in Breast Cancer
Approximately 25% of all breast cancer cases are attributed to familial susceptibility, with 5-10% of breast and ovarian cancer cases overall being linked to specific genetic mutations. 1
High-Penetrance Genetic Factors
- BRCA1 and BRCA2 are the most well-known high-penetrance breast cancer predisposition genes, accounting for 15-20% of the excess familial risk of breast cancer 1
- Women with BRCA1 mutations have a 65-80% lifetime risk of developing breast cancer and 37-62% risk of ovarian cancer 1
- Women with BRCA2 mutations have a 45-85% lifetime risk of breast cancer and 11-23% risk of ovarian cancer 1
- Male carriers of BRCA2 mutations have approximately 6% lifetime risk of breast cancer 1
- Other high-penetrance genes include:
- PTEN mutations (Cowden Syndrome) - 85% lifetime risk of breast cancer 1, 2
- TP53 mutations (Li-Fraumeni Syndrome) - 25% risk by age 74 1, 2
- CDH1 mutations (Hereditary Diffuse Gastric Cancer) - 39% lifetime risk of lobular breast cancer 1, 2
- STK11 mutations (Peutz-Jeghers Syndrome) - 32% risk by age 60 1, 2
Moderate-Penetrance Genetic Factors
- Several moderate-penetrance genes have been identified that confer intermediate risk of breast cancer 1, 2:
- CHEK2 mutations - approximately twofold increase in breast cancer risk
- ATM mutations - associated with intermediate risk
- PALB2 mutations - increasingly recognized as important in hereditary breast cancer
- BRIP1 mutations - associated with moderate breast cancer risk
Distribution of Genetic Factors
- The prevalence of BRCA mutation carriers in the general population is estimated at between 1/800 and 1/1000 1
- BRCA1 and BRCA2 mutation frequencies in breast cancer patients unselected for family history or age at onset are generally low (<1-7% for BRCA1 and 1-3% for BRCA2) 1
- Higher prevalence of mutations is associated with:
- Family history of breast or ovarian cancer
- Young age at onset
- Male breast cancer
- Multiple tumors (bilateral breast cancer or breast and ovarian cancer in the same patient) 1
- Population-specific mutations and founder effects exist, particularly among Ashkenazi Jews, where three major mutations account for ~10% of hereditary cases 1
Unexplained Genetic Factors
- Despite identification of multiple susceptibility genes, >70% of the genetic predisposition to breast cancer remains unexplained 1, 2
- Collectively, known high-penetrance genes (BRCA1, BRCA2, PTEN, TP53, CDH1, and STK11) account for no more than 25% of familial breast cancer cases 1, 2
Clinical Implications
- Genetic testing should be considered for individuals with:
- Breast cancer diagnosed at age ≤45 years
- Breast cancer diagnosed at age ≤50 years with family history
- Personal history of multiple primary breast cancers
- Male breast cancer
- Family history of breast and/or ovarian cancer
- Ashkenazi Jewish ancestry with breast, ovarian, or pancreatic cancer 2
- A negative BRCA1/2 test does not rule out hereditary breast cancer risk if family history remains suggestive 2
- Regular reassessment of family history is essential as new cancer events may alter risk assessment and testing recommendations 2
Important Considerations
- Interpretation of variants of uncertain significance remains challenging and requires expertise 2
- Penetrance varies significantly between high-risk genes (up to 80-90% lifetime risk) and moderate-risk genes (approximately twofold increase in risk) 2, 3
- Multigene panel testing is recommended when multiple genes could explain an inherited cancer syndrome 2
Genetic testing and counseling should be offered to individuals with suspected hereditary breast cancer to guide appropriate surveillance and risk-reduction strategies 1, 2.