Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

Anglesio, Michael S.; Arnold, Jeremy M.; George, Joshy; Tinker, Anna V.; Tothill, Richard W.; Waddell, Nicola; Simms, Lisa A.; Locandro, Bianca; Fereday, Sián; Traficante, Nadia; Russell, Peter; Sharma, Raghwa; Birrer, Michael J.; deFazio, Anna; Chenevix-Trench, Georgia; Bowtell, David D.L.

doi:10.1158/1541-7786.mcr-08-0193

Cited by 109 publications

(90 citation statements)

References 89 publications

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“…KRAS, ERBB2, and BRAF mutations have been reported previously in LGSC and SBT (10)(11)(12)(13)(14) and the identification of NRAS added another member of the Ras signaling pathway that is commonly mutated in LGSC. To gain a better estimate of frequency, we performed mutation analysis of the invasive region of a further 44 SBT-EOC cases, 53 purely SBT, and 53 EOC cases without adjacent borderline (Table 4; and Supplementary Information).…”

Section: Nras Mutations Are Confined To Invasive Cancersmentioning

confidence: 75%

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Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver

Emmanuel

Chiew

George

et al. 2014

Clinical Cancer Research

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111

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Purpose: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinumbased chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies.Experimental Design: We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling.Results: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC.Conclusion: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents. Clin Cancer Res; 20(24); 6618-30. Ó2014 AACR.

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Section: Nras Mutations Are Confined To Invasive Cancersmentioning

confidence: 75%

“…In contrast, lowgrade serous carcinomas (LGSC) typically have wild-type TP53 (9) and are thought to arise in a step-wise fashion from a subset of serous borderline tumors (SBT). Activating mutations of the MAPK pathway are present at a high rate in both SBTs and LGSCs (10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver

Emmanuel

Chiew

George

et al. 2014

Clinical Cancer Research

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111

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“…The following datasets were used: “Tumor Glioma Kawaguchi” (GSE43378), “Tumor Breast Chin” (GSE69031) 50 , “Tumor Colon Sieber-Smith“ (GSE14333 + GSE17538 minus identical samples), “Tumor Lymphoma Hummel” 51 , “Tumor Ovarian Anglesio” 52 . Probes considered for analyses were: ATF4: 200779_at, CD2: 205831_at, CD3D: 213539_at, IDO1: 210029_at, IFNG: 210354_at, IRF1: 202531_at, TDO2: 205943_at, WARS: 200629_at.…”

Section: Methodsmentioning

confidence: 99%

“…MEFs eIF2α S51A/S51A (AA-MEFs) and the corresponding controls, MEFs eIF2α S51/S (SS-MEFs) 53 were obtained from the R. Kaufman laboratory. Cells were cultivated in DMEM (Gibco) supplemented with 10% FCS (Gibco), 100 U/ml penicillin and 100 µg/ml streptomycin (Gibco).…”

Section: Methodsmentioning

confidence: 99%

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

et al. 2018

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Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful immunosuppressive mechanism hijacked by tumors for protection against immune destruction. However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid Trp. Trp is incorporated into proteins after it is attached to its tRNA by tryptophanyl-tRNA synthestases. As the tryptophanyl-tRNA synthestases compete for Trp with the Trp-catabolizing enzymes, the balance between these enzymes will determine whether Trp is used for protein synthesis or is degraded. In human cancers expression of the Trp-degrading enzymes indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2) was positively associated with the expression of the tryptophanyl-tRNA synthestase WARS. One mechanism underlying the association between IDO1 and WARS identified in this study is their joint induction by IFNγ released from tumor-infiltrating T cells. Moreover, we show here that IDO1- and TDO2-mediated Trp deprivation upregulates WARS expression by activating the general control non-derepressible-2 (GCN2) kinase, leading to phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) and induction of activating transcription factor 4 (ATF4). Trp deprivation induced cytoplasmic WARS expression but did not increase nuclear or extracellular WARS levels. GCN2 protected the cells against the effects of Trp starvation and enabled them to quickly make use of Trp for proliferation once it was replenished. Computational modeling of Trp metabolism revealed that Trp deficiency shifted Trp flux towards WARS and protein synthesis. Our data therefore suggest that the upregulation of WARS via IFNγ and/or GCN2-peIF2α-ATF4 signaling protects Trp-degrading cancer cells from excessive intracellular Trp depletion.

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“…SBOTs and LGSCs share common mutations in KRAF, BRAF, ERBB2 supporting the hypothesis that SBOT might potentially progress to LGSC [14][15][16]. The hypothesis suggesting that BOTs are a precursor state for LGSC is now accepted, although clinical and molecular studies are still necessary to understand the mechanism and risk factors.…”

Section: Introductionmentioning

confidence: 85%

In Ovo Progression of Borderline Ovarian Tumors

Meynier¹,

Undurraga²,

Jc³

et al. 2017

J Oncol Transl Res

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Objective: Borderline ovarian tumors (BOTs) are generally considered to be non-invasive tumors with low malignancy potential. However, studies show that BOTs have the ability to progress to low-grade carcinomas and gain the potential to invade surrounding tissue and to metastasize. Here, we investigate whether a patient derived serous BOT (SBOT) could progress in low-grade serous carcinoma (LGSC) through in vitro and in ovo characterization.Methods: Ovarian cancer cell line from a SBOT, named OCAM, were isolated and characterized by PCR, migration assay and chick chorioallantoic membrane (CAM) assay.Results: OCAM cells express carcinoma characteristics and form a tumor in CAM. Moreover, OCAM cells get into membrane of chicken suggesting invasive properties. Conclusion:SBOTs could a precursor of LGSC involving consequences in adaptation of treatment provided by clinician.

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Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

Cited by 109 publications

References 89 publications

Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver

Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

In Ovo Progression of Borderline Ovarian Tumors

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