A Novel Algorithm for Simplification of Complex Gene Classifiers in Cancer

Wilson, Raphael A.; Teng, Ling; Bachmeyer, Karen M.; Bissonnette, Mei Lin Z.; Husain, Aliya N.; Parham, David M.; Triche, Timothy J.; Wing, Michele R.; Gastier‐Foster, Julie M.; Barr, Frederic G.; Hawkins, Douglas S.; Anderson, James R.; Skapek, Stephen X.; Volchenboum, Samuel L.

doi:10.1158/0008-5472.can-13-0324

Cited by 4 publications

(3 citation statements)

References 22 publications

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“…There has been abundant research to evaluate whether gene expression profiling can be used to risk-stratify cancer patients at diagnosis. First demonstrated to be feasible in breast cancer [7], this prognostic approach has been evaluated and validated in other human cancers [8,9], including paediatric malignancies such as neuroblastoma [10][11][12], rhabdomyosarcoma [13][14][15], and leukaemia [16,17]. Several small ES genome-wide profiling studies have been reported, and non-overlapping candidate prognostic biomarkers were identified [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of Ewing sarcoma tumours reveals the prognostic importance of tumour–stromal interactions: a report from the Children's Oncology Group

Volchenboum

Andrade

Huang

et al. 2015

The Journal of Pathology CR

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Relapse of Ewing sarcoma (ES) can occur months or years after initial remission, and salvage therapy for relapsed disease is usually ineffective. Thus, there is great need to develop biomarkers that can predict which patients are at risk for relapse so that therapy and post‐therapy evaluation can be adjusted accordingly. For this study, we performed whole genome expression profiling on two independent cohorts of clinically annotated ES tumours in an effort to identify and validate prognostic gene signatures. ES specimens were obtained from the Children's Oncology Group and whole genome expression profiling performed using Affymetrix Human Exon 1.0 ST arrays. Lists of differentially expressed genes between survivors and non‐survivors were used to identify prognostic gene signatures. An independent cohort of tumours from the Euro‐Ewing cooperative group was similarly analysed as a validation cohort. Unsupervised clustering of gene expression data failed to segregate tumours based on outcome. Supervised analysis of survivors versus non‐survivors revealed a small number of differentially expressed genes and several statistically significant gene signatures. Gene‐specific enrichment analysis demonstrated that integrin and chemokine genes were associated with survival in tumours where stromal contamination was present. Tumours that did not harbour stromal contamination showed no association of any genes or pathways with clinical outcome. Our results reflect the challenges of performing RNA‐based assays on archived bone tumour specimens. In addition, they reveal a key role for tumour stroma in determining ES prognosis. Future biological and clinical investigations should focus on elucidating the contribution of tumour:micro‐environment interactions on ES progression and response to therapy.

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Section: Introductionmentioning

confidence: 99%

Gene expression profiling of Ewing sarcoma tumours reveals the prognostic importance of tumour–stromal interactions: a report from the Children's Oncology Group

Volchenboum

Andrade

Huang

et al. 2015

The Journal of Pathology CR

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“…On the other hand, the nCounter assay allows for RNA extracted from FFPE tissues to be analyzed for gene expression. This approach shows excellent correlation with Taqman based RT-PCR approach (19), and RNA expression quantified by nCounter has been used to discriminate FN from FP RMS (20). The nCounter assay has also been used and validated in other tumor types such as breast cancer and neuroblastoma (21, 22).…”

Section: Discussionmentioning

confidence: 99%

Clinical Application of Prognostic Gene Expression Signature in Fusion Gene–Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group

Hingorani

Missiaglia

Shipley

et al. 2015

Clinical Cancer Research

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Purpose Pediatric rhabdomyosarcoma has two common histological subtypes: embryonal (ERMS) and alveolar (ARMS). PAX/FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology while fusion gene-negative (FN) ARMS patients are clinically similar to ERMS patients. A five-gene expression signature (MG5) previously identified two diverse risk groups within the fusion-gene negative RMS (FN-RMS) patients but this has not been independently validated. The goal of the current study was to test whether expression of the MG5 metagene, measured using a technical platform that can be applied to routine pathology material, would correlate with outcome in a new cohort of patients with FN-RMS. Experimental Design Cases were taken from the Children's Oncology Group (COG) D9803 study of children with intermediate-risk RMS and gene expression profiling for the MG5 genes was performed using the nCounter assay. The MG5 score was correlated with clinical and pathological characteristics as well as overall and event-free survival. Results MG5 standardized score showed no significant association with any of the available clinical-pathological variables. The MG5 signature score showed a significant correlation with overall (N=57; HR 7.3 95%CI[1.9-27.0], p=0.003) and failure-free survival (N=57; HR 6.1 95%CI[1.9-19.7], p=0.002). Conclusions This represents the first, validated molecular prognostic signature for children with FN-RMS who otherwise have intermediate-risk disease. The capacity to measure the expression of a small number of genes in routine pathology material and apply a simple mathematical formula to calculate the MG5 metagene score provides a clear path toward better risk-stratification in future, prospective clinical trial.

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“…Comparisons of genomewide mRNA expression reveals that RMSp and RMSn show distinct expression profiles, and that ERMS is indistinguishable from ARMSn within the larger RMSn group [16, 23, 24]. Further, mRNA expression profiles can identify distinct outcome groups within RMSp or within each COG risk strata [23, 25], as well as predicting PAX-FOXO1 fusion status [26]. Studies of RMSn identified an mRNA expression signature derived from the weighted expression of five genes ( EPHA2, EED , NELF, CBS and EPB41L4B ) that can distinguish patient outcomes [19].…”

Section: Mrna Expression Signatures Correlate With Outcomes For Rmsnmentioning

confidence: 99%

Molecular diagnostics in the management of rhabdomyosarcoma

Arnold

Barr

2017

Expert Review of Molecular Diagnostics

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Introduction A classification of rhabdomyosarcoma (RMS) with prognostic relevance has primarily relied on clinical features and histologic classification as either embryonal or alveolar RMS. The PAX3-FOXO1 and PAX7-FOXO1 gene fusions occur in 80% of cases with the alveolar subtype and are more predictive of outcome than histologic classification. Identifying additional molecular hallmarks that further subclassify RMS is an active area of research. Areas Covered The authors review the current state of the PAX3-FOXO1 and PAX7-FOXO1 fusions as prognostic biomarkers. Emerging biomarkers, including mRNA expression profiling, MYOD1 mutations, RAS pathway mutations and gene fusions involving NCOA2 or VGLL2 are also reviewed. Expert commentary Strategies for modifying RMS risk-stratification based on molecular biomarkers are emerging with the potential to transform the clinical management of RMS, ultimately improving patient outcomes by tailoring therapy to predicted patient risk and identifying targets for novel therapies.

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A Novel Algorithm for Simplification of Complex Gene Classifiers in Cancer

Cited by 4 publications

References 22 publications

Gene expression profiling of Ewing sarcoma tumours reveals the prognostic importance of tumour–stromal interactions: a report from the Children's Oncology Group

Gene expression profiling of Ewing sarcoma tumours reveals the prognostic importance of tumour–stromal interactions: a report from the Children's Oncology Group

Clinical Application of Prognostic Gene Expression Signature in Fusion Gene–Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group

Molecular diagnostics in the management of rhabdomyosarcoma

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