Recurrent ESR1–CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers

Veeraraghavan, Jamunarani; Tan, Ying; Cao, Xi; Kim, Jin Ah; Wang, Xian; Chamness, Gary C.; Maiti, Sourindra N.; Cooper, Laurence J.N.; Edwards, Dean P.; Contreras, Alejandro; Hilsenbeck, Susan G.; Chang, Eric C.; Schiff, Rachel; Wang, Xiao Song

doi:10.1038/ncomms5577

Cited by 125 publications

(166 citation statements)

References 48 publications

(54 reference statements)

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“…ESR1-CCDC170 was recently reported to markedly increase cell motility and anchorage-independent growth, reduced endocrine sensitivity, and enhanced xenograft tumor formation (Veeraraghavan et al 2014). The mechanistic studies suggest that CCDC170 engages the GAB1 signalosome to potentiate growth factor signaling and enhance cell motility (Veeraraghavan et al 2014). Additionally, STAT3-PTRF has been reported to be present in uterus/cervix cancer (Ojesina et al 2014).…”

Section: Wwwgenomeorgmentioning

confidence: 99%

“…It is plausible that many of these gene fusions may be passenger aberrations corresponding to recurrent amplicons. However, a subset may represent potentially relevant gene fusions in breast cancer as exemplified by ESR1 translocations (Veeraraghavan et al 2014). Additionally, while the majority of gene fusions reside in commonly altered regions, there is still a subset of recurrent and functionally recurrent gene fusions that are not the by-product of a copy number event and therefore may warrant further exploration.…”

Section: Wwwgenomeorgmentioning

confidence: 99%

“…4, 5) have been reported to be involved in hormone therapy resistance, exemplifying the potential biological significance of these candidates (Li et al 2013). ESR1-CCDC170 was recently reported to markedly increase cell motility and anchorage-independent growth, reduced endocrine sensitivity, and enhanced xenograft tumor formation (Veeraraghavan et al 2014). The mechanistic studies suggest that CCDC170 engages the GAB1 signalosome to potentiate growth factor signaling and enhance cell motility (Veeraraghavan et al 2014).…”

Section: Wwwgenomeorgmentioning

confidence: 99%

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INTEGRATE: gene fusion discovery using whole genome and transcriptome data

et al. 2015

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While next-generation sequencing (NGS) has become the primary technology for discovering gene fusions, we are still faced with the challenge of ensuring that causative mutations are not missed while minimizing false positives. Currently, there are many computational tools that predict structural variations (SV) and gene fusions using whole genome (WGS) and transcriptome sequencing (RNA-seq) data separately. However, as both WGS and RNA-seq have their limitations when used independently, we hypothesize that the orthogonal validation from integrating both data could generate a sensitive and specific approach for detecting high-confidence gene fusion predictions. Fortunately, decreasing NGS costs have resulted in a growing quantity of patients with both data available. Therefore, we developed a gene fusion discovery tool, INTEGRATE, that leverages both RNA-seq and WGS data to reconstruct gene fusion junctions and genomic breakpoints by split-read mapping.

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Section: Wwwgenomeorgmentioning

confidence: 99%

Section: Wwwgenomeorgmentioning

confidence: 99%

Section: Wwwgenomeorgmentioning

confidence: 99%

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INTEGRATE: gene fusion discovery using whole genome and transcriptome data

et al. 2015

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“…Oncogenic receptor AR variants（Pca) [24][25] ; ER pro-neoplastic signaling [26][27] , neoplastic ESR1-CCDC170 fusion(also oncogenic receptor ERalpha fusion)（breast cancer) 7,28 ;GRβ aberrant signaling（Cushing's disease,erythrocytosis, GR + breast cancer, Nelson's syndrome) [29][30][31] ; FSH/FSH receptor oncogenic signaling（preneoplastic ovarian surface epithelial cells)…”

Section: Steroid Receptorsmentioning

confidence: 99%

EpCAM- AN OLD CANCER ANTIGEN, TURNED ONCOGENIC RECEPTOR AND ITS TAGETING IMMUNOTHERAPY

Zhu

2018

UJPR

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EpCAM is a cell adhesion molecule. Its structure, its expression and the oncogenic potential, and its signaling network and target therapy were in concise reviewed. In recent advances,in addition to PI3K/akt and Raf/MAPK pathway involving in cell survival,anti-apoptosis and proliferation,and malignant initiation and progression(see figure by Zhu,1986-91), three distinct pathway are illustrated: EpCAM/E-cadherin-catenin-actin cytoskeleton, EpCAM/ wint-catenin signaling and its major EpCAM/ nuclear signaling presented by Munz M in 2004. Moreover, more accumulated data are needed in detail mechanism. The data may provide its cancer biology and clinical targeting therapy benefits.

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“…Genomic rearrangements are also rare but have been reported. For example, ESR1-CCDC170 and ESR1-YAP1 fusion genes have been identified and contribute to an endocrine resistant phenotype , Veeraraghavan et al, 2014. The prevalence of ESR1 mutations in these studies ranged from 14-54%, and taken together, 29/187 (21%) of metastatic samples harboured an ESR1 mutation in the ligand binding domain (Jeselsohn et al, 2015).…”

Section: Mechanisms Underlying Endocrine Resistancementioning

confidence: 99%

Intratumour heterogeneity in the development and progression of breast cancer

Kutasovic¹

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The extent of intratumour heterogeneity and its clinical implications are poorly understood.This thesis addresses this theme of tumour heterogeneity with a broad focus on invasive lobular carcinomas of the breast. More specifically the focus will be on studying the various mechanisms of deregulation of E-cadherin, the morphological and phenotypic variation mixed ductal lobular carcinomas, and finally heterogeneity of metastatic progression.Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype, accounting for 10-15% of the all breast cancers, and is the most common 'special type'.Biologically, the most distinguishing feature of ILC is the loss of the cellular adhesion molecule E-cadherin (absent in up to 90% of ILC), and this is considered fundamental to development of the characteristic infiltrative growth pattern. The deregulation of Ecadherin is not fully understood, and so this thesis aims to investigate the mechanisms of E-cadherin deregulation in tumourigenesis. Co-localised with E-cadherin at the cell membrane are a series of proteins (including ECT2, RacGAP1 and N-WASP) which regulate the actin cytoskeleton; the expression of these proteins was investigated using immunohistochemistry (IHC) of breast cancer tissue microarrays (Chapter 3). Differences in cytoplasmic expression and localisation of these molecules were found between different histological types and clinicopathological parameters that warrant further investigation. It remains unclear whether these molecules contribute to deregulating cell adhesion in vivo.Mixed ductal-lobular carcinomas (MDL) display both ductal and lobular morphology, and are a clear example of intratumour morphological heterogeneity. It is hypothesised that these different components evolve from a common ancestor and diverge following deregulation of the E-cadherin complex. To address this hypothesis, a cohort of 82 MDLs was studied for clinical, morphological and molecular features (Chapter 4). Key findings include: i) MDLs more frequently co-exist with ductal carcinoma in situ (DCIS) than lobular carcinoma in situ (LCIS); ii) the E-cadherin-catenin complex was often normal in the ductal component but deregulated in the lobular component; iii) E-cadherin deregulation was different to that seen in classic ILC, which are typically completely negative for this marker, not aberrant; iv) Epithelial to mesenchymal transition marker expression was not associated with E-cadherin deregulation. Exome sequencing was performed to investigate clonal relationships between the different intratumour morphologies, and identify iii mechanisms underlying the change from a 'ductal' to a more infiltrative 'lobular' growth pattern. Preliminary analysis revealed that i) all morphological components within a case are clonally related; ii) divergence of the morphological components may occur early during tumour evolution (where there are both DCIS and LCIS present) or later during tumour progression (cases with only DCIS detectible); and iii) mutations were identi...

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Recurrent ESR1–CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers

Cited by 125 publications

References 48 publications

INTEGRATE: gene fusion discovery using whole genome and transcriptome data

INTEGRATE: gene fusion discovery using whole genome and transcriptome data

EpCAM- AN OLD CANCER ANTIGEN, TURNED ONCOGENIC RECEPTOR AND ITS TAGETING IMMUNOTHERAPY

Intratumour heterogeneity in the development and progression of breast cancer

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