c l i n i c a l f o l i o s : d i s c u s s i o n

Breast Cancer Genetics



Related narrative: Breast Cancer: Genetics

Five to ten percent of breast cancers, affecting up to 18,000 women per year, result from defunctionalizing mutations of genes which normally protect ("tumor suppressor genes") against malignant transformation of breast epithelial cells. These autosomal dominant mutated genes are passed on to progeny through either mother or father, and half the offspring of such a carrier will inherit the gene. Female carriers of the gene will have a 50-90% lifetime chance of developing breast cancer. Such cancers often occur at a young age. The recognition and study of high risk familial pedigrees led, in the 1990's, to the identification of some of the more common of these dysfunctional genes. The breast cancer gene now called BRCA1 is responsible for 20-40% of familial cases, and a second gene, BRCA2 accounts for another 10-30%. Other undiscovered genes account for the remaining 30-70%. Other rare mutations (p53, PTEN, AR, ATN, RB-1) account for a few percent.

The BRCA1 gene is located on the long arm of chromosome 17 (17q21), and the BRCA2 gene is found on the long arm of chromosome 13. The proteins coded for by the normal BRCA genes have a negative regulatory effect on cell growth and play a direct role in repairing damaged or mutated DNA. The latter "gatekeeper" function maintains genomic stability. Mutated (usually by truncation of gene length) BRCA genes lose normal functionality and allow accumulation of other genetic defects which lead to uncontrolled, abnormal cell growth and cancer. In the general population, 1 in 800 individuals carry a mutated BRCA gene, but in certain populations (Ashkenazi/eastern European Jews and certain Icelandic pedigrees thus far studied) there is a much higher incidence (1:50-100). There is also an associated higher risk of ovarian cancer in BRCA2 mutation carriers. There is also an increased risk of prostate, pancreas and male breast (BRCA2) cancers. The two BRCA genes account for 30-70% of genetically related breast cancers. The remaining cases are linked to a variety of other genetic causes.

The p53 tumor suppressor gene, found on chromosome 17 like BRCA1, is a negative regulator of cell growth and plays an important role in programmed cell death (apoptosis). By slowing the cell cycle, the p53 gene is thought to allow time for DNA repair before cell replication. The damaged p53 allows persistence of damaged DNA and is associated with tumor aggressiveness and poor clinical outcome. Mutation of p53 is one of the most common genetic abnormalities in tumors (found in 50%) and is associated with breast, colon, bladder, lung, prostate, leukemias and lymphomas. Defective p53 decreases responsiveness of resulting cancers to chemotherapy and radiotherapy. Germ line mutation in p53 is associated with the rare Li-Fraumeni syndrome (LFS), consisting of early onset breast cancer, childhood soft tissue sarcoma, osteosarcoma, leukemia, brain cancer and adrenocortical cancer. There are often multiple primary tumors. LFS has a high penetrance (expression in those with the gene), but is involved in less than 1% of breast cancers.

Another tumor suppressor gene, PTEN, found on chromosome 10(q22-23), is implicated in Cowden's syndrome, consisting of dermatoses, mucosal papillomas, hamartomas, breast, GI and thyroid tumors. Affected individuals have a high incidence of breast cancer (25-50% lifetime risk), but the syndrome accounts for only a small percent of hereditary breast cancers.

The ataxia telangiectasia (AT) gene located on chromosome 11 (q22-23) is also associated with an increased incidence of breast cancer (5X) in a small number of individuals. It produces a protein which plays a role in cell cycle control. The gene is an autosomal recessive, and when homozygous causes neurological deficits, telangiectasias, immunodeficiency and hypersensitivity to radiation and radiomimetic drugs.

Somatic (as opposed to germ line) genetic alterations occur locally within tumors. The HER2/neu gene encodes for the protein tyrosine kinase, which is homologous with human epidermal growth factor receptor (CERBB2). In patients with stage II (node positive) breast cancer, overexpression of HER2/neu is associated with increased relapse, decreased survival and is a marker for resistance to chemotherapy. An antibody against the ERBB2 protein can increase (by 15%) response rates. HER2/neu overexpression is also associated with poorer prognosis in gastric, prostate and lung cancer.

Several other somatic genetic alterations have been associated with breast cancer, including the c-myc oncogene (amplified in 1/3 of breast cancers), H-ras proto-oncogene point mutation, p55 (often associated with HER2/neu overexpression), and retinoblastoma gene (RB-1), a tumor suppressor gene altered in 15-20% of breast cancer patients. Overexpression/amplification of other genes (c-myc oncogene, H-ras proto-oncogene, HER2/neu) also play a role in many cancers.

The tumors of patients with hereditary BRCA1 breast cancer tend to be higher histological grade with increased mitoses and aneuploidy, have less in situ component and are less likely to be ER+, and have an increased incidence of contralateral breast cancers. BRCA2 breast cancers tend to be similar to sporadic tumors. Reports are mixed on the aggressiveness of such tumors, with some studies showing a similar stage for stage treatment response and survival and others showing a worse prognosis. Prophylactic bilateral mastectomy decreases the risk in affected individuals by about 90%. On the other hand, early breast cancer has a 90% cure rate and annual screening mammography and examination may confer a similar advantage (10% chance of dying of breast cancer without prophylactic mastectomy) on sporadic and hereditary breast cancer. Genetic factors in both sporadic and hereditary continue to be elucidated, along with new, more precisely targeted treatment strategies. Social issues of testing and effect of the information on insurability continue to evolve.


Townsend: Sabiston Textbook of Surgery, 16th ed., Copyright 2001 W. B. Saunders Company.

Offit K, in Abeloff: Clinical Oncology, 2nd ed., Copyright 2000 Churchill Livingstone, Inc., 138-147,2055,2056.


This page was last modified on 18-Sep-2002.