Clinical application of prognostic gene expression signature in fusion gene-negative rhabdomyosarcoma: A report fromthe children's oncology group

Pooja Hingorani, Edoardo Missiaglia, Janet Shipley, James R. Anderson, Timothy J. Triche, Mauro Delorenzi, Julie Gastier-Foster, Michele Wing, Douglas S. Hawkins, Stephen X. Skapek

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX-FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas 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 this 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 pathologic characteristics as well as overall and event-free survival. Results: MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N 1/4 57; HR, 7.3; 95% CI, 1.9-27.0; P 1/4 0.003) and failure-free survival (N 1/4 57; HR, 6.1; 95% CI, 1.9-19.7; P 1/4 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 simplemathematical formula to calculate theMG5metagene score provides a clear path toward better risk stratification in future prospective clinical trials.

Original languageEnglish (US)
Pages (from-to)4733-4739
Number of pages7
JournalClinical Cancer Research
Volume21
Issue number20
DOIs
StatePublished - Oct 15 2015

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Rhabdomyosarcoma
Gene Fusion
Transcriptome
Pathology
Gene Expression Profiling
Genes
Disease-Free Survival
Histology
Research Design
Clinical Trials
Pediatrics
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Clinical application of prognostic gene expression signature in fusion gene-negative rhabdomyosarcoma : A report fromthe children's oncology group. / Hingorani, Pooja; Missiaglia, Edoardo; Shipley, Janet; Anderson, James R.; Triche, Timothy J.; Delorenzi, Mauro; Gastier-Foster, Julie; Wing, Michele; Hawkins, Douglas S.; Skapek, Stephen X.

In: Clinical Cancer Research, Vol. 21, No. 20, 15.10.2015, p. 4733-4739.

Research output: Contribution to journalArticle

Hingorani, P, Missiaglia, E, Shipley, J, Anderson, JR, Triche, TJ, Delorenzi, M, Gastier-Foster, J, Wing, M, Hawkins, DS & Skapek, SX 2015, 'Clinical application of prognostic gene expression signature in fusion gene-negative rhabdomyosarcoma: A report fromthe children's oncology group', Clinical Cancer Research, vol. 21, no. 20, pp. 4733-4739. https://doi.org/10.1158/1078-0432.CCR-14-3326
Hingorani, Pooja ; Missiaglia, Edoardo ; Shipley, Janet ; Anderson, James R. ; Triche, Timothy J. ; Delorenzi, Mauro ; Gastier-Foster, Julie ; Wing, Michele ; Hawkins, Douglas S. ; Skapek, Stephen X. / Clinical application of prognostic gene expression signature in fusion gene-negative rhabdomyosarcoma : A report fromthe children's oncology group. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 20. pp. 4733-4739.
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abstract = "Purpose: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX-FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas 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 this 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 pathologic characteristics as well as overall and event-free survival. Results: MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N 1/4 57; HR, 7.3; 95{\%} CI, 1.9-27.0; P 1/4 0.003) and failure-free survival (N 1/4 57; HR, 6.1; 95{\%} CI, 1.9-19.7; P 1/4 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 simplemathematical formula to calculate theMG5metagene score provides a clear path toward better risk stratification in future prospective clinical trials.",
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T1 - Clinical application of prognostic gene expression signature in fusion gene-negative rhabdomyosarcoma

T2 - A report fromthe children's oncology group

AU - Hingorani, Pooja

AU - Missiaglia, Edoardo

AU - Shipley, Janet

AU - Anderson, James R.

AU - Triche, Timothy J.

AU - Delorenzi, Mauro

AU - Gastier-Foster, Julie

AU - Wing, Michele

AU - Hawkins, Douglas S.

AU - Skapek, Stephen X.

PY - 2015/10/15

Y1 - 2015/10/15

N2 - Purpose: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX-FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas 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 this 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 pathologic characteristics as well as overall and event-free survival. Results: MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N 1/4 57; HR, 7.3; 95% CI, 1.9-27.0; P 1/4 0.003) and failure-free survival (N 1/4 57; HR, 6.1; 95% CI, 1.9-19.7; P 1/4 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 simplemathematical formula to calculate theMG5metagene score provides a clear path toward better risk stratification in future prospective clinical trials.

AB - Purpose: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX-FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas 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 this 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 pathologic characteristics as well as overall and event-free survival. Results: MG5 standardized score showed no significant association with any of the available clinicopathologic variables. The MG5 signature score showed a significant correlation with overall (N 1/4 57; HR, 7.3; 95% CI, 1.9-27.0; P 1/4 0.003) and failure-free survival (N 1/4 57; HR, 6.1; 95% CI, 1.9-19.7; P 1/4 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 simplemathematical formula to calculate theMG5metagene score provides a clear path toward better risk stratification in future prospective clinical trials.

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