An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers

Natrajan, Rachael; Weigelt, Britta; Mackay, Alan; Geyer, Felipe C.; Grigoriadis, Anita; Tan, David S.P.; Jones, Chris; Lord, Christopher J.; Vatcheva, Radost; Rodríguez‐Pinilla, Socorro María; Palacios, José; Ashworth, Alan; Reis‐Filho, Jorge S.

doi:10.1007/s10549-009-0501-3

Cited by 144 publications

(160 citation statements)

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“…The genomic landscape of TNBCs is characterized by frequent and numerous DNA copy number losses and gains, suggesting a form of genomic instability (Table 1) [9,11,[31][32][33]. Gains/ amplifications and overexpression of BRAF, CDK6, CDKN2A, CCNE1, E2F, EGFR, FGFR1, FGFR2, IGFR1, KIT, MET, MYC, PDGFRA, and PIK3CA are also often encountered in TNBC [9,32,33].…”

Section: Triple-negative Breast Cancersmentioning

confidence: 99%

Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

et al. 2016

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Advances in DNA and RNA sequencing revealed substantially greater genomic complexity in breast cancer than simple models of a few driver mutations would suggest. Only very few, recurrent mutations or copy-number variations in cancer-causing genes have been identified. The two most common alterations in breast cancer are TP53 (affecting the majority of triple-negative breast cancers) and PIK3CA (affecting almost half of estrogen receptor-positive cancers) mutations, followed by a long tail of individually rare mutations affecting <1%–20% of cases. Each cancer harbors from a few dozen to a few hundred potentially high-functional impact somatic variants, along with a much larger number of potentially high-functional impact germline variants. It is likely that it is the combined effect of all genomic variations that drives the clinical behavior of a given cancer. Furthermore, entirely new classes of oncogenic events are being discovered in the noncoding areas of the genome and in noncoding RNA species driven by errors in RNA editing. In light of this complexity, it is not unexpected that, with the exception of HER2 amplification, no robust molecular predictors of benefit from targeted therapies have been identified. In this review, we summarize the current genomic portrait of breast cancer, focusing on genetic aberrations that are actively being targeted with investigational drugs.

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Section: Triple-negative Breast Cancersmentioning

confidence: 99%

Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

et al. 2016

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“…This type of BAC array platform has been shown to be as robust as, and to have comparable resolution with, high-density oligonucleotide arrays [25][26][27]. DNA labelling, array hybridizations and image acquisition were performed as previously described [28,29]. No whole-genome DNA amplification was performed.…”

Section: Microarray Comparative Genomic Hybridizationmentioning

confidence: 99%

“…No whole-genome DNA amplification was performed. aCGH data were preprocessed and analysed using an in-house R script (BACE.R) in R version 2.8.0, as previously described [28,30]. After filtering polymorphic BACs, a final dataset of 31 544 clones with unambiguous mapping information according to the March 2006 build (hg18) of the human genome (http://www.ensembl.org) was smoothed using the circular binary segmentation (cbs) algorithm [28,30].…”

Section: Microarray Comparative Genomic Hybridizationmentioning

confidence: 99%

“…aCGH data were preprocessed and analysed using an in-house R script (BACE.R) in R version 2.8.0, as previously described [28,30]. After filtering polymorphic BACs, a final dataset of 31 544 clones with unambiguous mapping information according to the March 2006 build (hg18) of the human genome (http://www.ensembl.org) was smoothed using the circular binary segmentation (cbs) algorithm [28,30]. A categorical analysis was applied to the BACs after classifying them as representing amplification (>0.45), gain (>0.08 and ≤0.45), loss (<−0.08) or no change, according to their cbssmoothed Log 2 ratio values [24,28,29,31,32].…”

Section: Microarray Comparative Genomic Hybridizationmentioning

confidence: 99%

“…After filtering polymorphic BACs, a final dataset of 31 544 clones with unambiguous mapping information according to the March 2006 build (hg18) of the human genome (http://www.ensembl.org) was smoothed using the circular binary segmentation (cbs) algorithm [28,30]. A categorical analysis was applied to the BACs after classifying them as representing amplification (>0.45), gain (>0.08 and ≤0.45), loss (<−0.08) or no change, according to their cbssmoothed Log 2 ratio values [24,28,29,31,32]. Threshold values were chosen to correspond to three standard deviations of the normal ratios obtained from the filtered clones mapping to chromosomes 1-22, assessed in multiple hybridizations between DNA extracted from a pool of male and female blood donors, as previously described [24].…”

Section: Microarray Comparative Genomic Hybridizationmentioning

confidence: 99%

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Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas

Geyer

Weigelt

Natrajan

et al. 2010

The Journal of Pathology

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187

159

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Cancers may be composed of multiple populations of submodal clones sharing the same initiating genetic lesions, followed by the acquisition of divergent genetic hits. Intra-tumour genetic heterogeneity has profound implications for cancer clinical management. To determine the extent of intra-tumour genetic heterogeneity in breast cancers, and whether the morphological diversity of breast cancers is underpinned by divergent genetic aberrations, we analysed the genomic profiles of microdissected, morphologically distinct components of six metaplastic breast carcinomas, tumours characterized by the presence of morphological areas with divergent differentiation. Each morphologically distinct component was separately microdissected and subjected to high-resolution microarray-based comparative genomic hybridization. Each component was also analysed by immunohistochemistry and in situ hybridization. Clonal relationship between the distinct components was tested by TP53 sequencing and human androgen receptor (HUMARA) X-chromosome inactivation assay. In the majority of cases, all morphologically distinct components from each case were clonal and displayed remarkably similar genetic profiles. In two cases, however, morphologically distinct components harboured specific genetic aberrations. In an adenosquamous carcinoma, the differences were such that only 20% of the genome harboured similar copy number changes. The squamous component displayed EGFR gene amplification, EGFR over-expression and lack of expression of hormone receptors, whereas the lobular component displayed the reverse pattern. The components of a biphasic spindle cell carcinoma harboured similar gains, losses, amplifications of 9p23 and 17q12 (HER2 ) and identical TP53 mutations, suggesting that these were relatively early events in the development of this tumour; however, each component displayed divergent focal amplifications. Importantly, the metastatic deposit of this case, despite harbouring a TP53 mutation identical to that found in the primary tumour, harboured additional specific focal amplifications. This proof-of-principle study provides direct evidence of intra-tumour genetic heterogeneity in breast cancers, and shows that in some cases morphological diversity may be underpinned by distinct genetic aberrations.

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