Key Points
Disease summary:
Breast cancer is a common disease panethnically. Approximately 15% to 20% of breast cancer is thought to cluster in families while only 5% to 10% is caused by single gene defects.
Ovarian cancer is far less common; approximately 10% to 25% of ovarian cancer is caused by single gene defects.
The monogenic form of breast and ovarian cancer, hereditary breast and ovarian cancer (HBOC), caused by mutation in BRCA1 and BRCA2 predisposes individuals and families to a high lifetime risk of breast and ovarian cancers as well as other cancers including the prostate and pancreas. BRCA1-specific lifetime risk for female breast cancer is 55% to 65%, with a 39% risk for ovarian cancer. BRCA2-specific lifetime risk for female breast cancer is 47%, with a 11% to 17% risk for ovarian cancer. BRCA-related male breast cancer risk is 7% with a 20% risk for prostate cancer.
CHEK2-related breast cancer is a more recently described disease association. Mutations in CHEK2 within the context of a strong family history of breast cancer pose an increased risk, though there is much controversy around actual risk assessments. Studies within a European population, where a single mutation is common (1100delC), report a baseline risk of 6%, with that risk increasing to 44% in families in which two other relatives have a breast cancer diagnosis.
Genome-wide association studies (GWAS) have identified 11 loci that have repeatedly been associated with breast cancer in at least two published studies, see Table 52-1. Interestingly a study by Bolton et al. found a risk association for ovarian cancer which overlaps the observed risk for breast cancer at 19q13.11. This may indicate a BRCA1– and/or BRCA2-associated pathway driving these risks. The other observed associations may ultimately reveal new cancer risk pathways or new insights into the one associated pathway.
| Loci | Reported Genes | Mapped Genes | Number of Studies |
|---|---|---|---|
| 16q12.1 | TOX3, TNRC9 | TOX3-CHD9 | 5 |
| 2q35 | Intergenic | TNP1-DIRC3 | 5 |
| 10q26.13 | FGFR2 | FGFR2, ATE1 | 9 |
| 5q11.2 | MAP3K1 | RPL26P19-MAP3K1 | 2 |
| 8q24.21 | Intergenic | SRRM1P-POU5F1B | 3 |
| 11p15.5 | LSP1 | LSP1 | 2 |
| 5p12 | Intergenic | FGF10-MRPS30-HCN1 | 3 |
| 6q25.1 | ESR1, C6orf97 | CCDC170-ESR1 | 4 |
| 10q21.2 | ZNF365 | ZNF365 | 2 |
| 3p24.1 | SLC4A7 | SLC4A7 | 2 |
| 19p13.11 | ABHD8, ANKLE1, C19orf62 | BABAM1 | 2 |
Hereditary basis:
HBOC is an autosomal dominant cancer predisposition syndrome; some individuals with a disease-causing mutation may not develop an associated cancer in their lifetime, giving the appearance that the disease may skip generations.
CHEK2 also exhibits an autosomal dominant pattern of inheritance, though with lower lifetime risk of disease, a family history may not be apparent.
Differential diagnosis:
It is important to distinguish the multiorgan system syndromes that include breast or ovarian cancer as a single feature (ie, Cowden syndrome, Li-Fraumeni syndrome, hereditary diffuse gastric cancer, Lynch syndrome, Peutz-Jeghers syndrome), from the familial tumor predispositions in which these tumors are often the only major finding (Table 52-2).
| Syndrome | Gene Symbol | Associated Findings |
|---|---|---|
| Hereditary breast and ovarian cancer syndrome (HBOC) | BRCA1, BRCA2 | BRCA1: Breast cancer with medullary histopathology, often estrogen receptor, progesterone receptor, and Her2 neu negative; ovarian cancer is typically epithelial. Pancreatic cancer BRCA2: Breast cancer that cannot be distinguished from sporadic cancer; 70% estrogen receptor and progesterone receptor positive, Her2 negative; ovarian cancer is typically epithelial. Melanoma and pancreatic cancer |
Cowden syndrome (PTEN syndromes) | PTEN | Benign and malignant breast, thyroid (typically follicular), and endometrial tumors. Additional features include macrocephaly, trichilemmomas, and papillomas |
| Li-Fraumeni syndrome | TP53 | Breast cancer, soft tissue sarcoma, leukemia, osteosarcoma, melanoma, as well as colon, pancreatic, adrenal cortical, and brain cancers |
| Hereditary diffuse gastric cancer | CDH1 | Lobular breast cancer and diffuse gastric cancer, typically signet-ring carcinoma or isolate cell-type carcinoma |
| Lynch syndrome | MLH1, MSH2, MSH6, PMS2, EPCAM | Colorectal, endometrial, and ovarian cancers |
| Peutz-Jeghers syndrome | STK11 | Gastrointestinal hamartomatous polyps with mucocutaneous pigmentation; breast cancer risk is increased though not a hallmark of the syndrome; Lifetime breast cancer risk 40% |
