Replication status as a possible marker for genomic instability in cells originating from genotypes with balanced rearrangements.

Abstract

Most allelic pairs of DNA replicate synchronously during the S phase of the cell cycle. However, some genes frequently replicate asynchronously, i.e. genes on the X chromosome and imprinted genes. Earlier studies demonstrated an asynchronous pattern of replication in some precancerous and invasive squamous carcinoma of the cervix as well as in multiple myeloma. A high rate of asynchronous pattern was found in: (1) lymphocytes of individuals with solid tumors as well as in other malignancies; (2) amniocytes of genotypes with an extra chromosome 13, 18 and 21; (3) lymphocytes of young mothers of a Down syndrome pregnancy. The asynchronic pattern was not locus specific and was found in all loci analyzed. These findings suggested that the mechanism controlling the temporal order of replication could be altered in cells with a genetic predisposition to cancer or aneuploidy. In this study, we found a higher rate of asynchronous pattern in genotypes carrying inversions 2 and 9 and in balanced heritable translocations (p < 0.01) and an even higher rate in cases with a de-novo balanced translocation. The process of tumorigenesis may begin with a change in cell cycle regulation which includes the duplication, replication and segregation of genetic information. However, it remains unknown whether individuals with balanced chromosome rearrangements are at increased risk of developing cancer later in life.