Replication Timing Aberration of KIF14 and MDM4/PI3KC2β Alleles and Aneuploidy as Markers of Chromosomal Instability and Poor Treatment Response in Ewing Family Tumor Patients

Abstract

Replication timing of allelic gene pairs is strictly regulated according to expression, genome stability, and epigenetic changes, and tumorigenesis may be associated with changes in the allelic replication in various tumors. Our aim was to determine whether such alterations had a prognostic value in Ewing's family tumor (EFT) patients. The KIF14 and MDM4/PI3KC2β and the centromeric satellite sequence of chromosomes 8 and 12 were used for replication timing assessments. Aneuploidy was assessed by enumerating the copy numbers of chromosomes 8 and 12. Replication timing and aneuploidy were detected cytogenetically using multicolors fluorescence in situ hybridization assay applied in 135 EFT. Patients with trisomy 8 presented an association with an asynchronous replication pattern (SD) of MDM4/PI3KC2β genes (p = 0.013). Trisomy 12 was associated with a synchronous pattern (DD) of KIF14 probe signals (p = 0.04). The DD synchronous replication pattern of KIF14 showed a correlation with age (p < 0.0001), and the SS synchronous replication pattern of the same locus showed a correlation with lung metastatic (p = 0.012). The subgroup of patients presenting with multiplet signals of MDM4/PI3KC2β showed an association with treatment response (p = 0.045) and age (p = 0.033). Replication pattern of KIF14 may, significantly, be associated with chromosomal instability as MDM4/PI3KC2β may be a considerably new marker of poor treatment response in EFT patients.

Keywords

replication timing / aneuploidy / chromosomal instability / poor treatment response / Ewing sarcoma

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