Breast Cancer

The incidence of breast cancer has increased recently especially among young women. The lifetime breast cancer risk for a woman reaching 80 years of age is about one in ten. Although many cases are sporadic, about 20% occur in familial aggregates, and perhaps 5%-10% show a segregation pattern indicative of an autosomal dominant trait. In addition, benign breast conditions exist that are associated with an increased risk of carcinoma development.

Benign Breast Disorders:

Hyperproliferative breast disorders of both the epithelial and connective tissues are common. Two predominantly epithelial benign hyperproliferations have been karyotipically characterized by chromosome banding analysis. The karyotypic abnormalities usually found are quite complex. Nevertheless, specific chromosome abnormalities in these tumor types are so consistent that they can be used to discriminate between tumor types and subtypes that are indistinguishable by histological examination alone.

Breast Carcinoma:

The studies of tumor cytogenetics using short term culture are likely to yield cytogenetic information in a high percentage of cases.

One of the prognostic markers in karyotypically complex carcinomas is the presence of gene amplification. This process is often indicated by the presence of double-minute chromosomes, homogeneously staining regions, or abnormally banded regions. Gene amplification usually indicates more aggressive disease and a poorer prognosis.

With fluorescent in situ hybridization (FISH) techniques, chromosomal aberrations associated with a specific tumor subtype, amplification of certain oncogenes, and deletion of certain tumor suppressor genes can be detected directly on the paraffin embedded tissue of excised tumors.

Breast Carcinoma:

p58:

Human p58 is a protein kinase structurally and functionally related to p34 cdc2. Alteration in gene expression appears to affect normal progression of the cell cycle. The gene encoding the protein kinase p58 has been recently mapped to chromosome 1p36 which is also implicated in some breast carcinoma. The p58 DNA analysis identifies specific genomic sequences in either metaphase chromosomes or interphase nuclei by in situ hybridization.

HER-2/neu:

The oncogene HER-2/neu, which is present as a single copy in normal cells, may be amplified 10-100 fold in approximately 30% of breast tumors. It has been mapped to chromosome 17 in the region 17q11.2-12.This phenomena is associated with poorer clinical response to treatment and shortened survival times. The HER-2/neu cosmid probe can be used to identify the amplification of the gene in both peripheral blood cells and paraffin embedded tissue sections.

P53-Tumor Suppressor Gene:

Mutations in the p53 tumor suppressor gene have been detected in about half of all cases of human cancer. The precise role of these mutations in tumors and neoplastic cell growth remains unclear as they may occur at different stages of tumor progression. Deletion of the p53 gene at chromosome 17 p13 also has been observed in breast cancer. The cytogenetic diagnostic test for the identification of deletions on chr17 includes the analysis of the p53 cosmid probe in either metaphase chromosomes or interphase nuclei by in situ hybridization.

Other Breast Cancer Genes:

BRCA1:

The autosomal dominant susceptibility gene for breast and ovarian cancer BRCA1 was recently localized and isolated on chromosome 17q21. Analyses of breast and ovarian kindreds identified an inherited mutation in approximately 50-60% of cases. Observation of loss of heterozygosity (LOH) for polymorphic markers on chromosome 17q in both familial and sporadic cases, has supported the hypothesis that BRCA1 is a tumor suppressor gene. Hence the BRCA1 gene has been shown to have a role in both familial and sporadic ovarian and breast cancer. More recent data suggest that additional tumor suppressor genes are likely to be present.

Currently direct diagnosis is only available for persons of Ashkenazi Jewish Ancestry. Linkage analysis can be done in some families.

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