ABSTRACT
BACKGROUND: Characterization of the biopathologic events underlying the early steps of breast carcinogenesis may have a dramatic impact on reducing breast cancer mortality. Genes involved in breast tumorigenesis are localized on chromosomes 1 and 17, and numeric aberrations of these chromosomes have been correlated with breast cancer tumorigenesis and progression. According to the field cancerization hypothesis, specific chromosome aberrations may be present in breast cancer and in normal-appearing adjacent tissue. The latter changes reflect the genomic damage that follows longterm carcinogenic exposure and precede the morphologically detectable neoplastic transformation. We hypothesize that detection of these aberrations in benign breast epithelium may provide a tool for molecular risk assessment. STUDY DESIGN: Using fluorescence in situ hybridization with centromere-specific probes, we determined the status of chromosomes 1 and 17 in fresh imprints of 28 samples of primary tumors and 54 samples of their surrounding uninvolved parenchyma taken from patients undergoing operations for breast carcinoma. Ten contralateral breast biopsy specimens collected from patients with previous breast carcinoma were also evaluated as a surrogate of a high-risk group to rule out the hypothesis that chromosomal aneusomy in tumor-adjacent tissue could be related to a paracrine effect of the primary tumor. Ten samples of benign breast tissue taken from patients at low risk were used as controls to define tolerance limits for aneusomy definition. RESULTS: Using threshold values of 40% of signal loss and 13% of signal gain to define chromosome aneusomy (ie, mean + 3 SDs of the control group signals), we found the following: 1) almost all primary breast tumors were aneusomic for chromosomes 1 and 17; 2) primary breast tumor and adjacent uninvolved parenchyma shared the same pattern of chromosomes 1 and 17 aneusomy in 66.7% of patients; and 3) chromosomes 1 and 17 aneusomies in contralateral benign breast samples from high-risk patients were not different from those in primary breast tumor or adjacent tissue samples. CONCLUSIONS: These results suggest that chromosomes 1 and 17 aneusomy may represent an intermediate biomarker of breast tumorigenesis potentially useful to detect patients at high risk of breast carcinoma who may benefit from preventive interventions.
Subject(s)
Aneuploidy , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast/pathology , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 1/genetics , Adult , Biopsy , Breast Neoplasms/pathology , Female , Humans , In Situ Hybridization, Fluorescence/statistics & numerical data , Incidence , Interphase/genetics , Middle Aged , Risk AssessmentSubject(s)
Aneuploidy , Multiple Myeloma/genetics , Paraproteinemias/genetics , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 17/metabolism , Chromosomes, Human, Pair 8 , Humans , In Situ Hybridization, Fluorescence , Interphase , Multiple Myeloma/diagnosis , Paraproteinemias/diagnosis , PrognosisABSTRACT
Direct interphase cytogenetic analysis was performed on nuclei of metastatic effusions from breast cancer using fluorescence ill situ hybridization (FISH). DNA probes specific for repetitive pericentromeric regions on chromosomes 6, 8, 17, and human midi-satellite probe specific for one locus on the short arm of chromosome 1 were used to determine chromosome copy numbers in interphase tumor cells. The analysis showed cytogenetic heterogeneity in most nuclei examined with multiple subpopulations and a range of 0-6 chromosome signals per cell. The presence of subclones in these fluids, their correlation with highly malignant phenotypes and the diagnostic and prognostic applications of this method is discussed.
