Hereditary Breast/Ovarian Cancer Genetic Testing

Breast/ovarian cancer is among the most common cancer types worldwide. In the general population, approximately 12% of women are expected to develop breast cancer. Many genes have been identified as being related to hereditary predisposition to breast and/or ovarian cancer. Among these genes, mutations in BRCA1 and BRCA2 are known to be responsible for approximately 50-85% of hereditary breast/ovarian cancer cases.

Breast Cancer

Breast cancer cases account for 25% of cancers diagnosed in women. It has been shown that 5-10% of all breast cancers are hereditary, and that mutations in the BRCA1 and BRCA2 genes are the mutations that most increase breast cancer risk.

Role of BRCA1 & BRCA2 Genes

BRCA1 and BRCA2, which are responsible for repairing DNA damage, are tumor suppressor genes. When mutated, they lose their function and become a factor that causes cancer formation — the exact opposite of their natural function.

More than 2,600 mutations have been identified in the BRCA1 and BRCA2 genes in total. These mutations are inherited in an autosomal dominant manner and show a high degree of penetrance. The general frequency of BRCA1 and BRCA2 mutation carriers in populations is approximately 1/500 – 1/1000.

Carrying a hereditary mutation in the BRCA1 or BRCA2 gene significantly increases the risk of developing breast, ovarian, and certain other cancers in both women and men (Table 1).

Table 1. Cancer Risk (by Age 70)

For Which Cases Should Genetic Testing Be Considered?

• Women diagnosed with breast and/or ovarian cancer
• Women with first- or second-degree relatives who have had breast or ovarian cancer
• Women with a first-degree relative diagnosed with breast cancer before age 50 or with bilateral breast cancer
• Multiple breast or ovarian cancer cases on the same side of the family
• A family member diagnosed with breast cancer before age 35
• A family member who has had both breast and ovarian cancer
• Men with a strong family history of breast/ovarian cancer

Obtaining a detailed and accurate family history is of great importance in determining an individual's risk of hereditary breast or ovarian cancer. Every step taken toward early cancer detection will help ensure the patient has access to preventive measures and proactive treatments. As a result, it will be possible to achieve a better prognosis for the disease.

1. Example Case with Moderate Risk for Hereditary Breast/Ovarian Cancer

There are two first- and second-degree relatives on the same side of the family who developed cancer before age 70.

2. Example Case with High Risk for Hereditary Breast/Ovarian Cancer

There are first- and second-degree relatives in the family with bilateral breast cancer (one before age 50) and relatives with ovarian cancer.

BRCA1 and 2 Genetic Analyses

1) BRCA1 and 2 Whole Gene Sequencing

In cases where the family history and/or clinical presentation points to a risk of hereditary breast/ovarian cancer, Whole Gene Sequencing is performed on the BRCA1 and BRCA2 genes. If a mutation is detected as a result of the sequencing analysis, it is recommended that other members of the patient's family also be tested for this familial mutation.

2) BRCA1 and 2 Deletion/Duplication Testing

In some cases, mutations may occur not in a small number of DNA bases but as the deletion or duplication of an entire region of the gene. This type of large deletion/duplication mutation has been observed to occur quite frequently in the BRCA1 and BRCA2 genes as well. However, such mutations cannot be reliably detected by Whole Gene Sequencing. Analysis of these mutations requires Deletion/Duplication Testing using the MLPA method.

3) Examination of Other Genes Associated with Breast/Ovarian Cancer

Besides BRCA1 and 2, the number of other genes found to be associated with the risk of developing breast and/or ovarian cancer is steadily increasing. Hereditary mutations in these other genes increase the risk not only of breast and/or ovarian cancer but also of other cancers such as melanoma, colon, pancreatic, and prostate cancer.

For women in whom no mutation is found in BRCA1 and BRCA2 testing but who have a strong family history of breast and/or ovarian cancer, panels performed using Next Generation Sequencing (NGS) may be recommended. These panels screen other predisposition genes that have been found to be associated with breast and/or ovarian cancer. If a mutation is detected as a result of this comprehensive NGS sequencing, it is recommended that the findings be confirmed using the Sanger Sequencing method.

Test Options for Breast / Ovarian Cancer

• Breast / Ovarian Cancer Panel – BASIC: Whole gene sequencing analysis of the BRCA1 and BRCA2 genes
• Breast / Ovarian Cancer Panel – BROAD: Full gene sequence analysis of the BRCA1, BRCA2, TP53, CDH1, CHEK2, PALB2, PTEN, and STK11 genes
• BRCA1 and BRCA2 Deletion / Duplication Testing: Using the MLPA method