A breast cancer meta-analysis of two expression measures of chromosomal instability reveals a relationship with younger age at diagnosis and high risk histopathological variables

David Endesfelder,Nicholas Mcgranahan,Charles Swanton,Zoltan Szallasi,Nicolai J Birkbak,Trevor A Graham,Maik Kschischo

doi:10.18632/oncotarget.298

Abstract

Breast cancer in younger patients often presents with adverse histopathological features, including increased frequency of estrogen receptor negative and lymph node positive disease status. Chromosomal instability (CIN) is increasingly recognised as an important prognostic variable in solid tumours. In a breast cancer meta-analysis of 2423 patients we examine the relationship between clinicopathological parameters and two distinct chromosomal instability gene expression signatures in order to address whether younger age at diagnosis is associated with increased tumour genome instability. We find that CIN, assessed by the two independently derived CIN expression signatures, is significantly associated with increased tumour size, ER negative or HER2 positive disease, higher tumour grade and younger age at diagnosis in ER negative breast cancer. These data support the hypothesis that chromosomal instability may be a defining feature of breast cancer biology and clinical outcome.

Highlights

Breast cancer in younger women has been shown to be associated with a worse prognosis than in older women [1,2,3]
We used a 12-gene genome instability signature defining genomically unstable (GU) breast cancers correlating gene expression data with chromosomal instability in breast cancer measured by DNA image cytometry, previously derived by Habermann and colleagues [12]
We assessed the representation of genomically unstable and genomically stable (GS) tumours based on the 12 gene signature within each CIN70 expression quartile (Figure 1)

Summary

Introduction

Breast cancer in younger women has been shown to be associated with a worse prognosis than in older women [1,2,3]. Chromosomal instability has been widely documented to be associated with poorer prognosis in solid tumours [5] and CIN induced by MAD2 expression promotes rapid tumour relapse following withdrawal of an oncogenic stimulus in animal models [6]. Pre-clinical models have in some cases demonstrated a deleterious impact upon cancer cell survival associated with excessive chromosomal instability initiated by spindle assembly checkpoint inactivation [7] and we and others have shown that aneuploidy has a negative impact upon cell proliferation [8]. Animal models have demonstrated that aneuploidy may confer a tumour suppressor effect in cancer prone mice[9]. Cahill and colleagues have suggested that whilst genetic instability may be advantageous under tumour-stromal selection pressures, a threshold may exist beyond which excessive instability becomes deleterious for cancer survival[10]

Methods

Results

Conclusion