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Breast and Ovarial Carcinoma - BRCA1, BRCA2, ATM, CHEK2, RAD51C

BRCA1, BRCA2

Clinical Features

Breast cancer is the most common tumor disease among women. Approximately 5-10% of patients have a family anamnesis indicating an inherited form with an autosomal dominant pattern of inheritance. In approx. 30-50% of these familial cases, mutations are found in the genes BRCA1 or BRCA2.

Carrier status for a BRCA1 or BRCA2 mutation coincides with a notably heightened risk of developing mamma and/or ovarian cancer in comparison to the general population. The average age of onset for carriers of mutations in the BRCA1 and/or BRCA2 gene is approximately 40 years - significantly below the average age of onset for sporadic mamma cancers with no positive family anamnesis. The following table depicts the cumulative risk for BRCA1 and BRCA2 mutations carriers:

While ovarian cancers often occur alongside mamma cancers in BRCA1-positive families (approx. 40%), ovarian cancers are less frequent in BRCA2-positive families (approx. 11%).  However, BRCA2 mutation carriers have an additional heightened risk of developing other tumors in comparison to the general population, especially pancreatic cancer, rare tumors of the oropharynx, colon cancer and lymphoma.

In BRCA1- and/or BRC2-negative families, age of onset is between 45 and 50 years of age; associated tumor diseases do not occur.

The CHEK2 gene (checkpoint kinase 2 gene) encodes for a protein kinase that is activated in response to DNA damages. CHEK2 has a regulatory function in the cell cycle and belongs to the group of tumor suppressor genes. Mutations in CHEK2 are associated with an increased risk for differential tumors, including breast, prostate and gastrointestinal cancer.
In contrast to patients with mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 which have a considerably elevated risk of developing breast cancer, female carriers of a heterozygous CHEK2 germline mutation have a lower risk. For the most frequent CHEK2 mutation (CHEK2*1100delC), a two- to three-fold increased risk is indicated for women developing breast cancer.

International Diagnostic Criteria

• An affected woman with breast and/or ovarian cancer before age 50.
• An affected woman with bilateral or multifocal breast and/or ovarian cancer  regardless of age of onset.
• Breast and/or ovarian cancers in the family indicating an autosomal dominant pattern of inheritance.
• A case of male breast cancer (an affected patient or incidence in the family) regardless of age of onset.

Detection rates BRCA1 and BRCA2 detection rates in patients presenting with different phenotypes and family history (Evans et al., J Med. Genet, 2010; Myriad Genetics data).

Genetic Information

The BRCA1 gene is located on chromosome 17 (17q21) and consists 22 exons, the BRCA2 gene is located on chromosome 13 (13q12) and consists 27 exons. ATM is located on chromosome 11 (11q22.3), and CHEK2 on chromosome 22 (22q12.1).

Prevalence

BRCA1    1 : 500 - 1 : 1000

BRCA2    < 1 : 1000

ATM: 1:40 000-1:100 000

RAD51C: Rare: 1.3% women of BRCA1/BRCA2 negative families

Diagnostic