Centromere 17 copy number gain reflects chromosomal instability in breast cancer

Kyoungyul Lee,Sejoon Lee,Min Hye Jang,Hyun Jeong Kim,Soomin Ahn,So Yeon Park

doi:10.1038/s41598-019-54471-w

Abstract

Chromosomal instability (CIN) is known to be associated with prognosis and treatment response in breast cancer. This study was conducted to determine whether copy number gain of centromere 17 (CEP17) reflects CIN, and to evaluate the prognostic and predictive value of CIN in breast cancer. CIN status was determined by summing copy number gains of four centromeric probes (CEP1, CEP8, CEP11, and CEP16) based on fluorescence in situ hybridization and CIN scores were calculated using next generation sequencing data. High CIN was associated with adverse clinicopatholgical parameters of breast cancer. Among them, positive HER2 status, high Ki-67 index and CEP17 copy number gain were found to be independent predictors of high CIN. High CIN was associated with poor clinical outcome of the patients in the whole group, as well as in luminal/HER2-negative and HER2-positive subtypes. CEP17 copy number was significantly higher in the high-CIN-score group than in the low-CIN-score group. A positive linear correlation between the mean CEP17 copy number and the CIN score was found. In conclusion, CEP17 copy number was confirmed as a useful predictor for CIN in breast cancer, and high CIN was revealed as an indicator of poor prognosis in breast cancer.

Highlights

Chromosomal instability (CIN) is known to be associated with prognosis and treatment response in breast cancer
We focused on the association of CEP17 copy number gain with CIN in breast cancer
Using the sum of CEP copy number gains as a unique measure of CIN, we showed that high CIN correlated significantly with aggressive clinicopathological parameters, including high T stage, lymph node metastasis, high histological grade, lymphovascular invasion, negative hormone receptor status, positive HER2 status, p53 overexpression, and high Ki-67 index

Summary

Introduction

Chromosomal instability (CIN) is known to be associated with prognosis and treatment response in breast cancer. This study was conducted to determine whether copy number gain of centromere 17 (CEP17) reflects CIN, and to evaluate the prognostic and predictive value of CIN in breast cancer. CEP17 copy number was confirmed as a useful predictor for CIN in breast cancer, and high CIN was revealed as an indicator of poor prognosis in breast cancer. We have shown that a gain in the CEP17 copy number is an indicator of poor prognosis in patients with luminal/HER2-negative breast cancers, suggesting that CEP17 copy number gain may reflect chromosomal instability (CIN) in breast cancer[10]. CIN is known to be associated with the clinical outcome and response to chemotherapy in breast cancer patients, it is not a useful biomarker because there is no practical method for its assessment[23]. We analyzed the correlation between CEP17 copy number and CIN scores, which were measured by analyzing copy number variations in generation sequencing (NGS) data in the second subset of breast cancer patients

Methods

Results

Conclusion