Replication timing aberrations and aneuploidy in peripheral blood lymphocytes of breast cancer patients.

BACKGROUND: Peripheral blood lymphocytes of patients with hematological malignancies or solid tumors, such as renal cell carcinoma or prostate cancer, display epigenetic aberrations (loss of synchronous replication of allelic counterparts) and genetic changes (aneuploidy) characteristic of the cancerous phenotype. This study sought to determine whether such alterations could differentiate breast cancer patients from cancer-free subjects. METHODS: The HER2 locus-an oncogene assigned to chromosome 17 whose amplification is associated with breast cancer (BCA)-and the pericentromeric satellite sequence of chromosome 17 (CEN17) were used for replication timing assessments. Aneuploidy was monitored by enumerating the copy numbers of chromosome 17. Replication timing and aneuploidy were detected cytogenetically using fluorescence in situ hybridization technology applied to phytohemagglutinin-stimulated lymphocytes of 20 women with BCA and 10 control subjects. RESULTS: We showed that both the HER2 and CEN17 loci in the stimulated BCA lymphocytes altered their characteristic pattern of synchronous replication and exhibited asynchronicity. In addition, there was an increase in chromosome 17 aneuploidy. The frequency of cells displaying asynchronous replication in the patients' samples was significantly higher (P < 10(-12) for HER2 and P < 10(-6) for CEN17) than the corresponding values in the control samples. Similarly, aneuploidy in patients' cells was significantly higher (P < 10(-9)) than that in the controls. CONCLUSIONS: The HER2 and CEN17 aberrant replication differentiated clearly between BCA patients and control subjects. Thus, monitoring the replication of these genes offers potential blood markers for the detection and monitoring of breast cancer.

Chromosome aberration and environmental physical activity: Down syndrome and solar and cosmic ray activity, Israel, 1990-2000.

The possibility that environmental effects are associated with chromosome aberrations and various congenital pathologies has been discussed previously. Recent advances in the collection and computerization of data make studying these potential associations more feasible. The aim of this study was to investigate a possible link between the number of Down syndrome (DS) cases detected prenatally or at birth yearly in Israel over a 10-year period compared with the levels of solar and cosmic ray activity 1 year before the detection or birth of each affected child. Information about 1,108,449 births was collected for the years 1990-2000, excluding 1991, when data were unavailable. A total of 1,310 cases of DS were detected prenatally or at birth--138 in the non-Jewish community and 1,172 in the Jewish population. Solar activity indices--sunspot number and solar radio flux 2,800 MHz at 10.7 cm wavelength for 1989-1999--were compared with the number of DS cases detected. Pearson correlation coefficients (r) and their probabilities (P) were established for the percentage of DS cases in the whole population. There was a significant inverse correlation between the indices of solar activity and the number of cases of DS detected--r=-0.78, P=0.008 for sunspot number and r=-0.76, P=0.01 for solar flux. The possibility that cosmophysical factors inversely related to solar activity play a role in the pathogenesis of chromosome aberrations should be considered. We have confirmed a strong trend towards an association between the cosmic ray activity level and the incidence of DS.

The clinical application of spectral karyotyping (SKY) in the analysis of prenatally diagnosed extra structurally abnormal chromosomes (ESACs).

OBJECTIVE: The prenatal detection of de novo extra structurally abnormal chromosomes (ESACs) presents a challenge because the associated risk for congenital anomaly ranges from 100% to practically none, depending on the chromosomal origin. Despite the use of standard cytogenetic techniques and even fluorescence in situ hybridization (FISH), the origin of some ESACs often remains elusive. Spectral karyotyping (SKY) is a molecular cytogenetic technique based on the simultaneous analysis of all chromosomes using a unique probe mix that allows the rapid identification of all chromosomes in 24 colors. The purpose of this study was to evaluate the use of SKY in the characterization of prenatally diagnosed de novo ESACs. METHODS: This series includes five cases of de novo ESACs detected prenatally in routine amniocentesis samples performed for advanced maternal age. Cases of inherited ESACs or ESACs defined by standard cytogenetic techniques were excluded. RESULTS: SKY analysis yielded valuable information, particularly in cases of nonsatellited ESACs: a der(18) and a ring(Y). In a case of a unisatellited der(15), SKY corroborated data obtained by standard cytogenetic techniques and FISH. Finally, in two cases of small bisatellited chromosomes, SKY was noncontributory. CONCLUSIONS: While SKY may be a valuable tool in some cases, especially nonsatellited and ring ESACs, it does have limitations and should be used judiciously in conjunction with other cytogenetic techniques.