Hereditary Breast Cancer Syndromes
Hereditary Breast-Ovarian Cancer Syndrome
BRCA1 and BRCA2 are large genes that are responsible for the majority of hereditary breast and ovarian cancer. These two genes are present in all individuals and function as tumor suppressor genes. When a mutation is present in one of these genes individuals are at a significantly higher risk of breast cancer (estimated to be) over a woman's lifetime, as well as a significantly higher risk of ovarian cancer (Men carrying a BRCA1 and BRCA2 mutations are at modestly increased risk of prostate cancer.
Nearly 2,000 distinct mutations and sequence variations have been described in BRCA1 and BRCA2. There is a high frequency of specific germline mutations, 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 in individuals of Ashkenazi Jewish descent. Up to 30% of breast cancer cases in women from this ethnic group diagnosed with breast cancer under the age of 40, 40% of breast cancer families and 60% of breast/ovarian cancer families carry one of these germline mutations. A high frequency of specific BRCA1 mutations has been found in other ethnic groups. One such example is the 999del15 BRCA2 mutation in Iceland.
Li-Fraumeni Syndrome
Breast cancer is a component of the rare Li-Fraumeni Syndrome (LFS), caused by mutations in the p53 gene. This syndrome is characterized by premenopausal breast cancer in combination with a family history of childhood sarcoma, brain tumors, leukemia and adrenocortical carcinoma. Tumors in these families tend to occur in childhood and early adulthood and often present as multiple cancers in the same individual. Approximately 50% of women with Li-Fraumeni syndrome develop breast cancer.
Cowden's Syndrome
Cowden's syndrome is characterized by the finding of breast cancer, gastrointestinal malignancies and thyroid disease (both benign and malignant). Lifetime estimates of breast cancer in women with Cowden's syndrome range from 25% to 50%. Similar to other forms of hereditary breast cancer, onset is often at young ages and may be bilateral. Skin manifestations are also common and may include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. The history of these characteristic skin findings on physical examination in addition to a history of breast cancer raises the suspicion of Cowden's. Germline mutations in the PTEN gene are responsible for this syndrome.
Ataxia Telangiectasia
Ataxia Telangiectasia (AT) is an autosomal recessive disorder that is characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that approximately 1% of the general population may be heterozygote carriers of the ATM gene. Individuals who are homozygous for ATM are at increased risk of malignancies, especially hematologic malignancies. A number of epidemiological studies have also suggested an increased risk of breast cancer among female carriers.
Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome (PJS) is an early onset autosomal dominant disorder characterized by melanocytic macules on the lips, perioral, and buccal regions, and multiple gastrointestinal polyps, both hamartomatous and adenomatous. Analyses have also shown that patients with this syndrome have a very high risk of developing breast, gastrointestinal, and other malignancies.
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