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.
Grinberg-Rashi
Helena
H
Department of Human Molecular Genetics & Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Cytron
Samuel
S
Gelman-Kohan
Zully
Z
Litmanovitch
Talia
T
Avivi
Lydia
L
D000328:Adult; D000368:Aged; D000782:Aneuploidy; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17; D020732:Cytogenetic Analysis; D042522:DNA Replication Timing / Q000235:genetics*; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D055815:Young Adult