Chromosome 17 centromere amplification and chromosomal instability (CIN) in breast cancer: Pathogenic and therapeutic implications

Abstract

Chromosomal instability (CIN) is present in variable degrees in a significant percentage (up to 90%) of cancers and often portends adverse outcomes. However, it has not been incorporated in clinical practice as a prognostic marker due to the lack of standardization and proof of clinical utility of assays to measure it, as well as uncertainties regarding optimal cut-offs. Amplification of the centromeric region of chromosome 17 as measured by In Situ Hybridization (ISH) of the CEP17 probe is used clinically as part of the ISH assay for HER2 status determination in breast cancer in cases with intermediate (2+) result of HER2 protein expression by immunohistochemistry. CEP17 amplification concerns the centromeric area and rarely extends beyond it to involve polysomy of the whole chromosome. The association of CEP17 amplification with generalized CIN remains uncertain. Such association, if confirmed, could be an opportunity for a practical and clinically validated test of CIN in breast cancer. This paper explores the association of CIN with centromere 17 amplification and with centromere function in general, as well as the pathophysiology of centromeres/kinetochore function during mitosis that underlies their relationship with CIN in cancer and in breast cancer in particular.