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Breast Cancer Genetic Testing   


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  Since the discovery of the breast cancer gene (BRCA1) in 1994 (and later the BRCA2) there has been interest in the question of who should have the test performed. Most women do not have the gene and most breast cancers are not caused by the gene, but among women from families with multiple cases of breast or ovarian cancer (particularly if they occurred at young ages and particularly if they are Jewish) the odds that the cancer gene is responsible rises significantly. There are more genes constantly being identified that are associated with breast cancer (go here).
According to lifetime risk estimates for women in the general population, about 12 percent will develop breast cancer, compared with 50 to 85 percent  of women with an altered BRCA1 or BRCA2 gene (go here for the cancer risks associated with this gene).
The risk for some women may be lower. For ovarian cancer, lifetime risk estimates for women in the general population predict that 1.5 percent  will get ovarian cancer, compared with 5 to 40 percent for women with an altered BRCA1 gene, and 10 to 20 percent for women with an altered BRCA2 gene. Among individuals of Ashkenazi (Eastern European) Jewish descent, 2.5 percent will have an altered BRCA1 or BRCA2 gene. This is significantly more common than in the general population, where about 1 in 800 individuals (about 0.1 percent) will have an alteration in BRCA1 or BRCA2.

The NCCN has a detailed guide for assessing genetic high risk women for breast or ovarian cancer here. The Medicare guidelines are here. To calculate the risk of carrying the BRCA genes for breast cancer go  here.

In 1996, the American Society of Clinical Oncology (ASCO) adopted a statement recommending that genetic susceptibility testing be offered in the setting of a "strong family history of cancer or very early onset of disease" and when the results will influence medical management. To aid clinicians in evaluating a woman's probability of carrying a BRCA1 or BRCA2 mutation, Myriad Genetic Laboratories makes available its observations of mutations in women according to their personal and family histories of cancer.

ASCO has stated that genetic susceptibility testing is most likely to be of clinical value in individuals with a greater than 10% probability of carrying a BRCA mutation. Clinicians may use this table to determine a patient's probability of carrying a mutation and whether genetic susceptibility testing may be warranted. tables risk if not Jewish,   risk if Jewish.

     The best information on the breast cancer genes and the role of screening is  from the NCI.   You need to understand the basic genetics of breast cancer and who should be  screened. A probability is table is posted. In St. Petersburg, we generally refer patients to the genetics counselors at USF (1-813-979-6769) also look at the BRACA web site. The NCCN has an excellent section on genetics and breast and ovarian cancer (go here) The ACS has a recent update (go here.)

The role of the mutation is quite complicated, consider the following study:

Inheritance of a mutant BRCA1 or BRCA2 gene (numbers 113705 and 600185, respectively, in Online Mendelian Inheritance in Man, a catalogue of inherited diseases) confers a lifetime risk of breast cancer of 50 to 85 percent and a lifetime risk of ovarian cancer of 15 to 45 percent. These germ-line mutations account for a substantial proportion of inherited breast and ovarian cancers, but it is likely that additional susceptibility genes will be discovered.

Certain pathological features can help to distinguish breast tumors with BRCA1 mutations from those with BRCA2 mutations. Tumors with BRCA1 mutations are high-grade cancers with a high mitotic index, "pushing" tumor margins (i.e., noninfiltrating, smooth edges), and a lymphocytic infiltrate, whereas tumors with BRCA2 mutations are heterogeneous, are often relatively high grade, and display substantially less tubule formation. The proportion of the perimeter with continuous pushing margins can distinguish both types of tumors from sporadic cases of breast cancer.Tumors with BRCA1 mutations are generally negative for both estrogen and progesterone receptors, whereas most tumors with BRCA2 mutations are positive for these hormone receptors. These differences imply that the mutant BRCA1 and BRCA2 genes induce the formation of breast tumors through separate pathways.

The BRCA1 and BRCA2 proteins participate in DNA repair and homologous recombination and probably other cellular processes. A cell with a mutant BRCA1 or BRCA2 gene, which therefore lacks functional BRCA1 or BRCA2 protein, has a decreased ability to repair damaged DNA. In animal models, this defect causes genomic instability.In humans, breast tumors in carriers of mutant BRCA1 or BRCA2 genes are characterized by a large number of chromosomal changes, some of which differ depending on the genotype.

In this study, we examined breast-cancer tissues from patients with BRCA1-related cancer, patients with BRCA2-related cancer, and patients with sporadic cases of breast cancer to determine whether there are distinctive patterns of global gene expression in these three kinds of tumors.

Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each other. An analysis of variance between the levels of gene expression and the genotype of the samples identified 176 genes that were differentially expressed in tumors with BRCA1 mutations and tumors with BRCA2 mutations. Given the known properties of some of the genes in this panel, our findings indicate that there are functional differences between breast tumors with BRCA1 mutations and those with BRCA2 mutations.

Conclusions. Significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. Our results suggest that a heritable mutation influences the gene-expression profile of the cancer. (N Engl J Med 2001;344:539-48.)