Genome and transcriptome delineation of two major oncogenic pathways governing invasive ductal breast cancer development
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Luay Aswad1,2, Surya Pavan Yenamandra1, Ghim Siong Ow1, Oleg Grinchuk1, Anna V. Ivshina1, Vladimir A. Kuznetsov1,2
1Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore
2School of Computer Engineering, Nanyang Technological University, Singapore 637553, Singapore
Vladimir A. Kuznetsov, e-mail: firstname.lastname@example.org
Keywords: invasive ductal carcinoma, low and high genetic grades, genome and transcriptome alterations, mutations, oncogenic pathway
Received: May 21, 2015 Accepted: September 25, 2015 Published: October 10, 2015
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.
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