Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.5543
Title: Genome and transcriptome delineation of two major oncogenic pathways governing invasive ductal breast cancer development
Authors: Aswad, L
Yenamandra, S.P
Ow, G.S
Grinchuk, O 
Ivshina, A.V
Kuznetsov, V.A
Keywords: Article
breast carcinoma
cancer grading
cancer prognosis
cell cycle
chromosome 16q
chromosome 22
classifier
controlled study
copy number variation
gene expression
genomics
human
human tissue
major clinical study
mitosis
oncogene
point mutation
polymerase chain reaction
somatic mutation
stem cell
transcriptomics
tumor classification
breast tumor
carcinogenesis
cohort analysis
female
genetics
human genome
middle aged
Paget nipple disease
pathology
prognosis
transcriptome
Breast Neoplasms
Carcinogenesis
Carcinoma, Ductal, Breast
Cohort Studies
Female
Genome, Human
Humans
Middle Aged
Prognosis
Transcriptome
Issue Date: 2015
Citation: Aswad, L, Yenamandra, S.P, Ow, G.S, Grinchuk, O, Ivshina, A.V, Kuznetsov, V.A (2015). Genome and transcriptome delineation of two major oncogenic pathways governing invasive ductal breast cancer development. Oncotarget 6 (34) : 36652-36674. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.5543
Rights: Attribution 4.0 International
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 celllike 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.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/180929
ISSN: 19492553
DOI: 10.18632/oncotarget.5543
Rights: Attribution 4.0 International
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