Genome and transcriptome delineation of two major oncogenic pathways governing invasive ductal breast cancer development.

Luay Aswad,Surya Pavan Yenamandra,Vladimir A Kuznetsov,Anna V Ivshina,Oleg Grinchuk,Ghim Siong Ow

doi:10.18632/oncotarget.5543

Abstract

Invasive ductal carcinoma (IDC) is a major histo-morphologic type of breast cancer. Histological grading (HG) of IDC is widely adopted by oncologists as a prognostic factor. However, HG evaluation is highly subjective with only 50%-85% inter-observer agreements. Specifically, the subjectivity in the assignment of the intermediate grade (histologic grade 2, HG2) breast cancers (comprising ~50% of IDC cases) results in uncertain disease outcome prediction and sub-optimal systemic therapy. Despite several attempts to identify the mechanisms underlying the HG classification, their molecular bases are poorly understood.We performed integrative bioinformatics analysis of TCGA and several other cohorts (total 1246 patients). We identified a 22-gene tumor aggressiveness grading classifier (22g-TAG) that reflects global bifurcation in the IDC transcriptomes and reclassified patients with HG2 tumors into two genetically and clinically distinct subclasses: histological grade 1-like (HG1-like) and histological grade 3-like (HG3-like). The expression profiles and clinical outcomes of these subclasses were similar to the HG1 and HG3 tumors, respectively. We further reclassified IDC into low genetic grade (LGG = HG1+HG1-like) and high genetic grade (HGG = HG3-like+HG3) subclasses. For the HG1-like and HG3-like IDCs we found subclass-specific DNA alterations, somatic mutations, oncogenic pathways, cell cycle/mitosis and stem cell-like expression signatures that discriminate between these tumors. We found similar molecular patterns in the LGG and HGG tumor classes respectively.Our results suggest the existence of two genetically-predefined IDC classes, LGG and HGG, driven by distinct oncogenic pathways. They provide novel prognostic and therapeutic biomarkers and could open unique opportunities for personalized systemic therapies of IDC patients.

Highlights

Invasive ductal carcinoma (IDC), the major histomorphologic type of breast cancer, is diagnosed in 180,000 women in the USA each year
The tumors consisted of the following histological grades: 32 Histological grade 1 (HG1), 183 Histological grade 2 (HG2) and 215 Histological grade 3 (HG3) tumor samples (Table 1A)
We proposed that HG2 tumors are genetically heterogeneous and include tumors which oncogenic pathways could be separated into two distinct subclasses similar to either HG1 or HG3 tumors

Summary

Introduction

Invasive ductal carcinoma (IDC), the major histomorphologic type of breast cancer, is diagnosed in 180,000 women in the USA each year. The morphological assessment of the degree of tumor cell differentiation, represented by tumor histological grades (HGs), has attracted much attention for its potential to elucidate the heterogeneities of breast carcinoma (BC) due to its powerful prognostic capability, relative low cost, and simple methodology [1,2,3,4,5]. Histological grading can be performed by combining cell morphology (nuclear polymorphism), tissue architecture (tubule formation) and visual assessment of the cell www.impactjournals.com/oncotarget proliferation rate (mitotic count), but prognostic value of the combination of these features is still being discussed [1,2,3, 5, 10]. The variability for the intermediate grade (histologic grade 2, HG2) breast cancers (comprising ~50% of IDC cases) is evident, resulting in uncertain disease outcome prediction and sub-optimal systemic therapy

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Discussion

Conclusion