What genes are associated with increased cancer risk?

Genes Associated with Increased Cancer Risk

Several high-penetrance and moderate-penetrance genes have been identified as significantly increasing cancer risk, particularly for breast and ovarian cancers. 1

High-Penetrance Cancer Susceptibility Genes

High-penetrance genes confer up to an 80% lifetime risk of developing cancer:

• BRCA1 and BRCA2: The most well-established genes associated with Hereditary Breast/Ovarian Cancer (HBOC) syndrome, conferring 50-85% lifetime risk of breast cancer and 10-40% risk of ovarian cancer 1

• TP53: Associated with Li-Fraumeni Syndrome, conferring up to 25% risk of breast cancer by age 74, along with increased risk of sarcoma, brain tumors, adrenocortical carcinoma, and leukemia 1, 2

• PTEN: Associated with PTEN Hamartoma Tumor Syndrome/Cowden Syndrome, conferring up to 85% lifetime risk of breast cancer and increased risk of thyroid and endometrial cancers 2

• CDH1: Associated with Hereditary Diffuse Gastric Cancer, conferring approximately 39% lifetime risk of lobular breast cancer and increased risk of diffuse gastric and colorectal cancers 1, 2

• STK11: Associated with Peutz-Jeghers Syndrome, conferring approximately 32% risk of breast cancer by age 60, along with increased risk of GI cancers, pancreatic cancer, and sex-cord stromal tumors 2

Moderate-Penetrance Cancer Susceptibility Genes

These genes confer a 2-5 fold increased risk of cancer:

• CHEK2: Confers approximately twofold increased risk of female breast cancer and 10-fold increase in male breast cancer 1, 2

• ATM: Associated with approximately 2.37-fold increased risk of breast cancer; biallelic mutations cause ataxia-telangiectasia 1, 2

• PALB2: Associated with increased risk of breast and pancreatic cancers; emerging evidence suggests higher risk than previously thought 1, 2

• BRIP1 (BACH1): Interacts with BRCA1 and confers about twofold increased risk of breast cancer; biallelic mutations cause Fanconi anemia type J 1, 2

• RAD51C and RAD51D: Potentially high-risk cancer predisposition genes in breast/ovarian cancer families 2

• BARD1: Emerging evidence supports its role in hereditary breast cancer 2, 3

Clinical Significance and Testing

• Despite identification of multiple susceptibility genes, >70% of familial breast cancer cases remain unexplained genetically 2, 4

• Multigene panel testing is recommended when multiple genes could explain an inherited cancer syndrome, as this approach is more cost-effective and comprehensive 1, 2

• 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 1, 2

Important Considerations

• A negative BRCA1/2 test does not rule out hereditary cancer risk if family history remains suggestive 2

• Interpretation of variants of uncertain significance remains challenging and requires expertise 2

• Penetrance varies significantly between high-risk genes (up to 80% lifetime risk) and moderate-risk genes (approximately twofold increase in risk) 1, 2

• Regular reassessment of family history is essential as new cancer events may alter risk assessment and testing recommendations 1, 2

• Tumor characteristics can help guide genetic testing; for example, BRCA1-related tumors tend to be triple-negative with high histologic grade, while BRCA2-related tumors more closely resemble sporadic tumors 1, 3