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Genetic Epidemiology

Several lines of evidence exist which support a role for genetic factors in breast cancer susceptibility. Twin studies provide data that suggest genetics may play a role with concordance rates of breast cancer occurrence between genetically identical monozygotic twins somewhat greater than those of dizygotic twins (17% versus 14%, respectively) (8). Segregation analyses are mathematical genetic analyses that investigate familial characteristics, possible modes of inheritance, and risk for disease using population-based data. A segregation analysis for breast cancer was performed using the Cancer and Steroid Hormone Study data that compared family history reports between 4,730 breast cancer cases and 4,688 controls (9). The results of this investigation provided evidence for the existence of a rare autosomal dominant allele (q=0.0033; estimated carrier prevalence, 1/152) leading to increased susceptibility to breast cancer. Furthermore, the effect of genotype on the risk of breast cancer was shown to be a function of a woman’s age, with the ratio of age-specific risks greatest at young ages. The proportion of cases with the susceptibility allele was predicted to be 36% among cases aged 20 to 29 years, and only 1% among cases aged 80 years or older.

Breast cancer cases with an autosomal dominant cancer susceptibility are a relatively herterogenous group (Table D).

Hereditary Breast Cancer
BRAC1 Breast/Ovary, Site Specific

Breast Cancer

Breast, ovarian, prostate and colon cancers
BRAC2 Breast/Ovary, Site Specific

Breast Cancer

Breast cancer, including male breast cancer, ovarian, prostate, melanoma and pancreatic cancer
TP53 Li-Fraumeni Sarcoma, breast and brain cancer, leukemia, lymphoma and adrenal cancer




Muir-Torre Colon, endometrial, ovarian, uroepithelial, biliary tract, breast cancer, sebaceous adenomas and keratoacanthomas
AT Ataxia telangiectasia (including heterozygotes) Leukemia, lymphoma, breast cancer
CD Cowden Disease Breast and thyroid cancer, multiple hamartomas of skin and GI tract
P-J Peutz-Jeghers GI hamartomas, mucocutaneous pigmentation, breast, ovarian and testicular tumors

Clinical investigations of familial aggregation have identified at least 7 genetic syndromes with an autosomal dominant pattern of inheritance that feature breast cancer (10). The most common include hereditary site-specific breast cancer and the breast-ovary syndrome. Rare genetic syndromes that also feature breast cancer include Li-Fraumeni syndrome, Muir-Torre syndrome, Cowden disease, Peutz-Jeghers syndrome, and Ataxia Telangectasia (10). Genetic linkage studies performed in families with four or more cases of breast cancer and at least one family member diagnosed at an early age provided evidence that two major genes for breast cancer susceptibility were located on chromosomes 17q and 13q, their corresponding names were BRCA1 and BRCA2 (11,12). The cancer risks associated with these genes in these families indicated not only an increase in risk for breast cancer, but also an increased risk for ovarian cancer (13). Mutations in the BRCA1 gene were also associated with a risk for colorectal and prostate cancer (13). The genes for the other known hereditary breast cancer syndromes have also been localized, and for some, deleterious mutations have been identified (see below).

Finding breast cancer susceptibility genes and mutations within them provide the ultimate evidence that genetics plays an important role in breast cancer development. The next challenge will be to determine the cellular functions of the protein products for each of these genes which will further our ability to create effective and targeted chemotherapeutic agents.

Genes and Breast Cancer

As with other cancers of epithelial origin, breast cancer is thought to develop through a series of genetic mutational events that begin in a single cell (Figure 1).

Normal Epithelium
In Situ Carcinoma

The initial event allows for increased cellular proliferation increasing the number of normal cells. This is then followed by additional mutations which permit development of hyperplasia, dysplasia, carcinoma and eventually, metastatic disease.

The genes involved in this process may be classified into four categories: 1) tumor suppressor genes, 2) proto-oncogenes, 3) DNA repair genes, and 4) carcinogen metabolism genes. The normal function of a tumor suppressor gene is to encode for a protein that controls cell growth, that of an proto-oncogene is to encode for a protein that promotes cell growth. When a tumor suppressor gene or oncogene is mutated, either through loss of a normal tumor suppressor gene or through a gain in function of a proto-oncogene, cell growth may be promoted. DNA repair genes encode for enzymes that restore the integrity of the DNA if it is damaged by radiation or carcinogens, or if mismatches occur during the replication process. Mutations in DNA repair genes which lead to a loss in function may accelerate the carcinogenic process by allowing mutations to accumulate. Genes encoding for enzymes that metabolize carcinogens can contribute to cancer development depending upon their efficiencies in performing their functions. The interaction of mutations or polymorphisms in these genes with the environment is necessary for cancer development. Thus, an environmental factor (exogenous or endogenous) appears to play the primary role in contributing to carcinogenesis in this case.

Mutations in tumor suppressor genes, proto-oncogenes, DNA repair genes and carcinogen metabolism genes may be acquired or inherited. Acquired mutations may occur as a result of exposure to radiation or a chemical carcinogen, or by chance alone during cellular replication. To date, mutations in tumor suppressor genes account for most known hereditary breast cancer syndromes, including BRCA1 and BRCA2 in hereditary site-specific breast cancer and breast-ovary syndrome, p53 in Li-Fraumeni syndrome, PTEN in Cowden disease, and the Peutz-Jeghers locus on 19p. The functions of the protein products of these genes is not well understood. The ATM gene involved in Ataxia Telangectasia and the genes that contribute to the cancer susceptibility in Muir-Torre syndrome (MSH2, MLH1, PMS1, and PMS2) may be classified as DNA repair genes.

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