Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

Holst, Frederik; Høivik, Erling A.; Gibson, William J.; Taylor-Weiner, Amaro; Schumacher, Steven E.; Asmann, Yan W.; Großmann, Patrick; Trovik, Jone; Necela, Brian M.; Thompson, E. Aubrey; Meyerson, Matthew; Beroukhim, Rameen; Salvesen, Helga B.; Cherniack, Andrew D.

doi:10.1038/srep25521

Cited by 13 publications

(10 citation statements)

References 56 publications

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“…Our detection of copy number shifts within ESR1 complements similar findings describing ‘truncating amplifications’ in endometrial cancer [ 21 ]. Of note, Holst et al link one truncating amplification to a gene fusion.…”

Section: Discussionsupporting

confidence: 87%

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer

Hartmaier

Trabucco²,

Priedigkeit

et al. 2018

Annals of Oncology

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BackgroundEstrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer.Patients and methodsTo identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287–395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots.ResultsWe identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3′ partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations.ConclusionsCollectively, these data indicate that N-terminal ESR1 fusions involving exons 6–7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.

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Section: Discussionsupporting

confidence: 87%

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer

Hartmaier

Trabucco²,

Priedigkeit

et al. 2018

Annals of Oncology

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“…Estrogen and its receptors are essential for sexual development and reproductive function. Previous studies have shown that ESR1 is closely related to the occurrence and development of various urogenital cancers [20][21][22][23], especially breast cancer [24,25] and endometrial cancer [26][27][28]. Recent studies have reported the important role of ESR1 in non-small-cell lung cancer (NSCLC) [29,30] and bladder cancer [31].…”

Section: Discussionmentioning

confidence: 99%

ESR1 as a recurrence-related gene in intrahepatic cholangiocarcinoma: a weighted gene coexpression network analysis

Chen

Yang

et al. 2021

Cancer Cell Int

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Background Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant hepatic tumor and has a high postoperative recurrence rate and a poor prognosis. The key roles of most tumor recurrence-associated molecules in iCCA remain unclear. This study aimed to explore hub genes related to the postsurgical recurrence of iCCA. Method Differentially expressed genes (DEGs) between iCCA samples and normal liver samples were screened from The Cancer Genome Atlas (TCGA) database and used to construct a weighted gene coexpression network. Module-trait correlations were calculated to identify the key module related to recurrence in iCCA patients. Genes in the key module were subjected to functional enrichment analysis, and candidate hub genes were filtered through coexpression and protein–protein interaction (PPI) network analysis. Validation studies were conducted to detect the “real” hub gene. Furthermore, the biological functions and the underlying mechanism of the real hub gene in iCCA tumorigenesis and progression were determined via in vitro experiments. Results A total of 1019 DEGs were filtered and used to construct four coexpression modules. The red module, which showed the highest correlations with the recurrence status, family history, and day to death of patients, was identified as the key module. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that genes in the red module were enriched in genes and pathways related to tumorigenesis and tumor progression. We performed validation studies and identified estrogen receptor 1 (ESR1), which significantly impacted the prognosis of iCCA patients, as the real hub gene related to the recurrence of iCCA. The in vitro experiments demonstrated that ESR1 overexpression significantly suppressed cell proliferation, migration, and invasion, whereas ESR1 knockdown elicited opposite effects. Further investigation into the mechanism demonstrated that ESR1 acts as a tumor suppressor by inhibiting the JAK/STAT3 signaling pathway. Conclusions ESR1 was identified as the real hub gene related to the recurrence of iCCA that plays a critical tumor suppressor role in iCCA progression. ESR1 significantly impacts the prognosis of iCCA patients and markedly suppresses cholangiocarcinoma cell proliferation, migration and invasion by inhibiting JAK/STAT3 signaling pathway.

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Section: Introductionmentioning

confidence: 99%

“…7,8 The role that estrogens play in the development of EC is further highlighted by the fact that germline variants in the estrogen receptor (ESR1) are associated with risk for EC (most strongly with the endometrioid subtype) 9 and that somatic ESR1 mutations are seen in primary EC. 10,11 FOXA2 is a member of the FOXA subfamily of forkhead box proteins that includes FOXA1, FOXA2 and FOXA3. 12,13 FOXA proteins bind DNA and act as pioneer and transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

Neff

Rush

Smith

et al. 2018

Intl Journal of Cancer

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FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N-terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E-cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C-terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E-cadherin (CDH1) expression and E-cadherin's potential role in epithelial-to-mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT-PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression.

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Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

Cited by 13 publications

References 56 publications

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer

ESR1 as a recurrence-related gene in intrahepatic cholangiocarcinoma: a weighted gene coexpression network analysis

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

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