Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor

Jinsheng Yu, Hrishikesh Deshmukh, Jacqueline E. Payton, Christopher Dunham, Bernd W. Scheithauer, Tarik Tihan, Richard A. Prayson, Abhijit Guha, Julia A. Bridge, Rosalie E. Ferner, Guy M. Lindberg, Rebecca J. Gutmann, Ryan J. Emnett, Lorena Salavaggione, David H. Gutmann, Rakesh Nagarajan, Mark A. Watson, Arie Perry

Research output: Contribution to journalArticle

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Abstract

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs. Experimental Design: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens. Results: aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05). Conclusions: Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients.

Original languageEnglish (US)
Pages (from-to)1924-1934
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number7
DOIs
StatePublished - Apr 1 2011

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Comparative Genomic Hybridization
Neurilemmoma
Survival
Biomarkers
Genes
Messenger RNA
DNA
Fluorescence In Situ Hybridization
Sarcoma
Real-Time Polymerase Chain Reaction
Research Design
Multivariate Analysis
Immunohistochemistry
RNA
Neoplasms
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor. / Yu, Jinsheng; Deshmukh, Hrishikesh; Payton, Jacqueline E.; Dunham, Christopher; Scheithauer, Bernd W.; Tihan, Tarik; Prayson, Richard A.; Guha, Abhijit; Bridge, Julia A.; Ferner, Rosalie E.; Lindberg, Guy M.; Gutmann, Rebecca J.; Emnett, Ryan J.; Salavaggione, Lorena; Gutmann, David H.; Nagarajan, Rakesh; Watson, Mark A.; Perry, Arie.

In: Clinical Cancer Research, Vol. 17, No. 7, 01.04.2011, p. 1924-1934.

Research output: Contribution to journalArticle

Yu, J, Deshmukh, H, Payton, JE, Dunham, C, Scheithauer, BW, Tihan, T, Prayson, RA, Guha, A, Bridge, JA, Ferner, RE, Lindberg, GM, Gutmann, RJ, Emnett, RJ, Salavaggione, L, Gutmann, DH, Nagarajan, R, Watson, MA & Perry, A 2011, 'Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor', Clinical Cancer Research, vol. 17, no. 7, pp. 1924-1934. https://doi.org/10.1158/1078-0432.CCR-10-1551
Yu, Jinsheng ; Deshmukh, Hrishikesh ; Payton, Jacqueline E. ; Dunham, Christopher ; Scheithauer, Bernd W. ; Tihan, Tarik ; Prayson, Richard A. ; Guha, Abhijit ; Bridge, Julia A. ; Ferner, Rosalie E. ; Lindberg, Guy M. ; Gutmann, Rebecca J. ; Emnett, Ryan J. ; Salavaggione, Lorena ; Gutmann, David H. ; Nagarajan, Rakesh ; Watson, Mark A. ; Perry, Arie. / Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 7. pp. 1924-1934.
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abstract = "Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs. Experimental Design: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens. Results: aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05). Conclusions: Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients.",
author = "Jinsheng Yu and Hrishikesh Deshmukh and Payton, {Jacqueline E.} and Christopher Dunham and Scheithauer, {Bernd W.} and Tarik Tihan and Prayson, {Richard A.} and Abhijit Guha and Bridge, {Julia A.} and Ferner, {Rosalie E.} and Lindberg, {Guy M.} and Gutmann, {Rebecca J.} and Emnett, {Ryan J.} and Lorena Salavaggione and Gutmann, {David H.} and Rakesh Nagarajan and Watson, {Mark A.} and Arie Perry",
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T1 - Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor

AU - Yu, Jinsheng

AU - Deshmukh, Hrishikesh

AU - Payton, Jacqueline E.

AU - Dunham, Christopher

AU - Scheithauer, Bernd W.

AU - Tihan, Tarik

AU - Prayson, Richard A.

AU - Guha, Abhijit

AU - Bridge, Julia A.

AU - Ferner, Rosalie E.

AU - Lindberg, Guy M.

AU - Gutmann, Rebecca J.

AU - Emnett, Ryan J.

AU - Salavaggione, Lorena

AU - Gutmann, David H.

AU - Nagarajan, Rakesh

AU - Watson, Mark A.

AU - Perry, Arie

PY - 2011/4/1

Y1 - 2011/4/1

N2 - Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs. Experimental Design: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens. Results: aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05). Conclusions: Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients.

AB - Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs. Experimental Design: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens. Results: aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05). Conclusions: Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients.

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