Hereditary breast and ovarian cancer syndrome

Hereditary breast and ovarian cancer (HBOC) syndrome is caused by a mutation to either BRCA1 or BRCA2 genes. These patients have an increased risk of breast cancer, ovarian cancer, pancreatic cancer and prostate cancer. However, these gene mutations are not the only cause of hereditary breast cancer or hereditary ovarian cancer. The estimate of their penetrance is extremely variable (about 30 and 70%) ⁶.

Terminology

As per scientific convention, the short names of genes are italicized i.e. BRCA1, but not their long names, i.e. breast cancer 1, and not their protein products which remain in plain font i.e. "BRCA1 protein" or "breast cancer 1 protein".

Epidemiology

The estimated prevalence of BRCA1/BRCA2 carriage is 1 in 550 (range 1 in 300-800) ³. 

Pathology

BRCA1 and BRCA2 are tumor suppressor genes that encode proteins involved in DNA repair. More than a thousand mutations to each gene have been detected, and cancer develops after the inheritance of a mutated BRCA1/BRCA2 gene from one parent, followed by a mutation to the second normal BRCA1/BRCA2 gene from the other parent ("two-hit hypothesis") ³.

The tumor suppressor genes BRCA1 and BRCA2 are located on chromosomes 17 and 13, respectively ⁵

The risk of specific cancer type above the general population risk varies depending on the mutation ¹:

• BRCA1 mutation

  • breast cancer: lifetime risk of 55-65%

    • second primary breast cancer: ~30% at 5 years

  • male breast cancer: 1-2%

  • ovarian cancer: lifetime risk of 40%

  • prostate cancer: lifetime risk of 9.5%

  • pancreatic cancer: ~2%

  • colorectal cancer: 5x increased risk if <50 years ⁴

  • primary fallopian tube carcinoma: relative risk up to 120 ⁵

  • primary peritoneal serous carcinoma: risk around 4% following risk-reducing salpingo-oophorectomy (RRSO) ⁵

• BRCA2 mutation

  • breast cancer: lifetime risk of 45%

    • second primary breast cancer: ~10% at 5 years

  • male breast cancer: ~7.5%

  • ovarian cancer: lifetime risk of 11-17%

  • prostate cancer: lifetime risk of 20%

  • pancreatic cancer: ~5%

  • colorectal cancer: no increased risk ^4​​

Comparison of BRCA1 and BRCA2 mutations

• although primary fallopian tube carcinoma, primary peritoneal serous carcinoma and colon carcinoma are associated with both BRCA1 and BRCA2 mutations, they are more strongly associated with BRCA1 mutations ⁵

• lifetime occurrence risk of prostate cancer is almost double with BRCA2 mutations in comparison to BRCA1 mutations (20% vs 9.5%) ⁵

• lifetime risk of ovarian cancer is around 2.5 to 3.5 times greater in the presence of BRCA1 over BRCA2 mutations (40% vs 11-17%) ⁵

• male breast cancer occurrence risk is more than 5.5 times greater with BRCA2 than BRCA1 mutations (6.8% vs 1.2%)