A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma

Yaping Shou, Douglas M. Robinson, Dereck D. Amakye, Kristine L. Rose, Yoon-Jae Cho, Keith L. Ligon, Thad Sharp, Asifa S. Haider, Raj Bandaru, Yuichi Ando, Birgit Geoerger, Franҫois Doz, David M. Ashley, Darren R. Hargrave, Michela Casanova, Hussein A. Tawbi, Jordi Rodon, Anne L. Thomas, Alain C. Mita, Tobey J. MacDonaldMark W. Kieran

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Purpose: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma. Experimental Design: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed. Results: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded. Conclusions: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment.

Original languageEnglish (US)
Pages (from-to)585-593
Number of pages9
JournalClinical Cancer Research
Volume21
Issue number3
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

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Medulloblastoma
Genes
Therapeutics
Neoplasms
Logistic Models
Propensity Score
Validation Studies
Computational Biology
Transcriptome
Paraffin
Formaldehyde
Research Design
Polymerase Chain Reaction
LDE225

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma. / Shou, Yaping; Robinson, Douglas M.; Amakye, Dereck D.; Rose, Kristine L.; Cho, Yoon-Jae; Ligon, Keith L.; Sharp, Thad; Haider, Asifa S.; Bandaru, Raj; Ando, Yuichi; Geoerger, Birgit; Doz, Franҫois; Ashley, David M.; Hargrave, Darren R.; Casanova, Michela; Tawbi, Hussein A.; Rodon, Jordi; Thomas, Anne L.; Mita, Alain C.; MacDonald, Tobey J.; Kieran, Mark W.

In: Clinical Cancer Research, Vol. 21, No. 3, 01.02.2015, p. 585-593.

Research output: Contribution to journalArticle

Shou, Y, Robinson, DM, Amakye, DD, Rose, KL, Cho, Y-J, Ligon, KL, Sharp, T, Haider, AS, Bandaru, R, Ando, Y, Geoerger, B, Doz, F, Ashley, DM, Hargrave, DR, Casanova, M, Tawbi, HA, Rodon, J, Thomas, AL, Mita, AC, MacDonald, TJ & Kieran, MW 2015, 'A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma', Clinical Cancer Research, vol. 21, no. 3, pp. 585-593. https://doi.org/10.1158/1078-0432.CCR-13-1711
Shou, Yaping ; Robinson, Douglas M. ; Amakye, Dereck D. ; Rose, Kristine L. ; Cho, Yoon-Jae ; Ligon, Keith L. ; Sharp, Thad ; Haider, Asifa S. ; Bandaru, Raj ; Ando, Yuichi ; Geoerger, Birgit ; Doz, Franҫois ; Ashley, David M. ; Hargrave, Darren R. ; Casanova, Michela ; Tawbi, Hussein A. ; Rodon, Jordi ; Thomas, Anne L. ; Mita, Alain C. ; MacDonald, Tobey J. ; Kieran, Mark W. / A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 3. pp. 585-593.
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abstract = "Purpose: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma. Experimental Design: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed. Results: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100{\%} concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded. Conclusions: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment.",
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T1 - A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma

AU - Shou, Yaping

AU - Robinson, Douglas M.

AU - Amakye, Dereck D.

AU - Rose, Kristine L.

AU - Cho, Yoon-Jae

AU - Ligon, Keith L.

AU - Sharp, Thad

AU - Haider, Asifa S.

AU - Bandaru, Raj

AU - Ando, Yuichi

AU - Geoerger, Birgit

AU - Doz, Franҫois

AU - Ashley, David M.

AU - Hargrave, Darren R.

AU - Casanova, Michela

AU - Tawbi, Hussein A.

AU - Rodon, Jordi

AU - Thomas, Anne L.

AU - Mita, Alain C.

AU - MacDonald, Tobey J.

AU - Kieran, Mark W.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - Purpose: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma. Experimental Design: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed. Results: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded. Conclusions: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment.

AB - Purpose: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma. Experimental Design: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed. Results: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded. Conclusions: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment.

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