Identification of plasma Complement C3 as a potential biomarker for neuroblastoma using a quantitative proteomic approach

Patrick Y. Kim, Owen Tan, Sonya M. Diakiw, Daniel Carter, Eric O. Sekerye, Valerie C. Wasinger, Tao Liu, Maria Kavallaris, Murray D. Norris, Michelle Haber, Lou Chesler, Alla Dolnikov, Toby N. Trahair, Nai Kong Cheung, Glenn M. Marshall, Belamy B. Cheung

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The majority of patients diagnosed with neuroblastoma present with aggressive disease. Improved detection of neuroblastoma cancer cells following initial therapy may help in stratifying patient outcome and monitoring for relapse. To identify potential plasma biomarkers, we utilised a liquid chromatography-tandem mass spectrometry-based proteomics approach to detect differentially-expressed proteins in serum from TH-MYCN mice. TH-MYCN mice carry multiple copies of the human MYCN oncogene in the germline and homozygous mice for the transgene develop neuroblastoma in a manner resembling the human disease. The abundance of plasma proteins was measured over the course of disease initiation and progression. A list of 86 candidate plasma biomarkers was generated. Pathway analysis identified significant association of these proteins with genes involved in the complement system. One candidate, complement C3 protein, was significantly enriched in the plasma of TH-MYCN+/+ mice at both 4 and 6weeks of age, and was found to be elevated in a cohort of human neuroblastoma plasma samples, compared to healthy subjects. In conclusion, we have demonstrated the suitability of the TH-MYCN+/+ mouse model of neuroblastoma for identification of novel disease biomarkers in humans, and have identified Complement C3 as a candidate plasma biomarker for measuring disease state in neuroblastoma patients. Biological significance: This study has utilised a unique murine model which develops neuroblastoma tumours that are biologically indistinguishable from human neuroblastoma. This animal model has effectively allowed the identification of plasma proteins which may serve as potential biomarkers of neuroblastoma. Furthermore, the label-free ion count quantitation technique which was used displays significant benefits as it is less labour intensive, feasible and accurate. We have been able to successfully validate this approach by confirming the differential abundance of two different plasma proteins. In addition, we have been able to confirm that the candidate biomarker Complement C3, is more abundant in the plasma of human neuroblastoma patient plasma samples when compared to healthy counterparts. Overall we have demonstrated that this approach can be potentially useful in the identification of biomarker candidates, and that further validation of the candidates may lead to the discovery of novel, clinically useful diagnostic tools in the detection of sub-clinical neuroblastoma.

LanguageEnglish
Pages1-12
Number of pages12
JournalJournal of Proteomics
Volume96
DOIs
Publication statusPublished - 16 Jan 2014
Externally publishedYes

Fingerprint

Complement C3
Biomarkers
Neuroblastoma
Proteomics
Plasmas
Blood Proteins
Identification (control systems)
Plasma (human)
Proteins
Liquid chromatography
Mass spectrometry
Labels
Tumors
Animals
Genes
Display devices
Cells
Association reactions
Personnel
Ions

Bibliographical note

Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Biomarker
  • Complement C3
  • Complement system
  • Neuroblastoma
  • Zinc-alpha2-glycoprotein
  • TH-MYCN+/+

Cite this

Kim, Patrick Y. ; Tan, Owen ; Diakiw, Sonya M. ; Carter, Daniel ; Sekerye, Eric O. ; Wasinger, Valerie C. ; Liu, Tao ; Kavallaris, Maria ; Norris, Murray D. ; Haber, Michelle ; Chesler, Lou ; Dolnikov, Alla ; Trahair, Toby N. ; Cheung, Nai Kong ; Marshall, Glenn M. ; Cheung, Belamy B. / Identification of plasma Complement C3 as a potential biomarker for neuroblastoma using a quantitative proteomic approach. In: Journal of Proteomics. 2014 ; Vol. 96. pp. 1-12.
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abstract = "The majority of patients diagnosed with neuroblastoma present with aggressive disease. Improved detection of neuroblastoma cancer cells following initial therapy may help in stratifying patient outcome and monitoring for relapse. To identify potential plasma biomarkers, we utilised a liquid chromatography-tandem mass spectrometry-based proteomics approach to detect differentially-expressed proteins in serum from TH-MYCN mice. TH-MYCN mice carry multiple copies of the human MYCN oncogene in the germline and homozygous mice for the transgene develop neuroblastoma in a manner resembling the human disease. The abundance of plasma proteins was measured over the course of disease initiation and progression. A list of 86 candidate plasma biomarkers was generated. Pathway analysis identified significant association of these proteins with genes involved in the complement system. One candidate, complement C3 protein, was significantly enriched in the plasma of TH-MYCN+/+ mice at both 4 and 6weeks of age, and was found to be elevated in a cohort of human neuroblastoma plasma samples, compared to healthy subjects. In conclusion, we have demonstrated the suitability of the TH-MYCN+/+ mouse model of neuroblastoma for identification of novel disease biomarkers in humans, and have identified Complement C3 as a candidate plasma biomarker for measuring disease state in neuroblastoma patients. Biological significance: This study has utilised a unique murine model which develops neuroblastoma tumours that are biologically indistinguishable from human neuroblastoma. This animal model has effectively allowed the identification of plasma proteins which may serve as potential biomarkers of neuroblastoma. Furthermore, the label-free ion count quantitation technique which was used displays significant benefits as it is less labour intensive, feasible and accurate. We have been able to successfully validate this approach by confirming the differential abundance of two different plasma proteins. In addition, we have been able to confirm that the candidate biomarker Complement C3, is more abundant in the plasma of human neuroblastoma patient plasma samples when compared to healthy counterparts. Overall we have demonstrated that this approach can be potentially useful in the identification of biomarker candidates, and that further validation of the candidates may lead to the discovery of novel, clinically useful diagnostic tools in the detection of sub-clinical neuroblastoma.",
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author = "Kim, {Patrick Y.} and Owen Tan and Diakiw, {Sonya M.} and Daniel Carter and Sekerye, {Eric O.} and Wasinger, {Valerie C.} and Tao Liu and Maria Kavallaris and Norris, {Murray D.} and Michelle Haber and Lou Chesler and Alla Dolnikov and Trahair, {Toby N.} and Cheung, {Nai Kong} and Marshall, {Glenn M.} and Cheung, {Belamy B.}",
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Kim, PY, Tan, O, Diakiw, SM, Carter, D, Sekerye, EO, Wasinger, VC, Liu, T, Kavallaris, M, Norris, MD, Haber, M, Chesler, L, Dolnikov, A, Trahair, TN, Cheung, NK, Marshall, GM & Cheung, BB 2014, 'Identification of plasma Complement C3 as a potential biomarker for neuroblastoma using a quantitative proteomic approach', Journal of Proteomics, vol. 96, pp. 1-12. https://doi.org/10.1016/j.jprot.2013.10.032

Identification of plasma Complement C3 as a potential biomarker for neuroblastoma using a quantitative proteomic approach. / Kim, Patrick Y.; Tan, Owen; Diakiw, Sonya M.; Carter, Daniel; Sekerye, Eric O.; Wasinger, Valerie C.; Liu, Tao; Kavallaris, Maria; Norris, Murray D.; Haber, Michelle; Chesler, Lou; Dolnikov, Alla; Trahair, Toby N.; Cheung, Nai Kong; Marshall, Glenn M.; Cheung, Belamy B.

In: Journal of Proteomics, Vol. 96, 16.01.2014, p. 1-12.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Identification of plasma Complement C3 as a potential biomarker for neuroblastoma using a quantitative proteomic approach

AU - Kim, Patrick Y.

AU - Tan, Owen

AU - Diakiw, Sonya M.

AU - Carter, Daniel

AU - Sekerye, Eric O.

AU - Wasinger, Valerie C.

AU - Liu, Tao

AU - Kavallaris, Maria

AU - Norris, Murray D.

AU - Haber, Michelle

AU - Chesler, Lou

AU - Dolnikov, Alla

AU - Trahair, Toby N.

AU - Cheung, Nai Kong

AU - Marshall, Glenn M.

AU - Cheung, Belamy B.

N1 - Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2014/1/16

Y1 - 2014/1/16

N2 - The majority of patients diagnosed with neuroblastoma present with aggressive disease. Improved detection of neuroblastoma cancer cells following initial therapy may help in stratifying patient outcome and monitoring for relapse. To identify potential plasma biomarkers, we utilised a liquid chromatography-tandem mass spectrometry-based proteomics approach to detect differentially-expressed proteins in serum from TH-MYCN mice. TH-MYCN mice carry multiple copies of the human MYCN oncogene in the germline and homozygous mice for the transgene develop neuroblastoma in a manner resembling the human disease. The abundance of plasma proteins was measured over the course of disease initiation and progression. A list of 86 candidate plasma biomarkers was generated. Pathway analysis identified significant association of these proteins with genes involved in the complement system. One candidate, complement C3 protein, was significantly enriched in the plasma of TH-MYCN+/+ mice at both 4 and 6weeks of age, and was found to be elevated in a cohort of human neuroblastoma plasma samples, compared to healthy subjects. In conclusion, we have demonstrated the suitability of the TH-MYCN+/+ mouse model of neuroblastoma for identification of novel disease biomarkers in humans, and have identified Complement C3 as a candidate plasma biomarker for measuring disease state in neuroblastoma patients. Biological significance: This study has utilised a unique murine model which develops neuroblastoma tumours that are biologically indistinguishable from human neuroblastoma. This animal model has effectively allowed the identification of plasma proteins which may serve as potential biomarkers of neuroblastoma. Furthermore, the label-free ion count quantitation technique which was used displays significant benefits as it is less labour intensive, feasible and accurate. We have been able to successfully validate this approach by confirming the differential abundance of two different plasma proteins. In addition, we have been able to confirm that the candidate biomarker Complement C3, is more abundant in the plasma of human neuroblastoma patient plasma samples when compared to healthy counterparts. Overall we have demonstrated that this approach can be potentially useful in the identification of biomarker candidates, and that further validation of the candidates may lead to the discovery of novel, clinically useful diagnostic tools in the detection of sub-clinical neuroblastoma.

AB - The majority of patients diagnosed with neuroblastoma present with aggressive disease. Improved detection of neuroblastoma cancer cells following initial therapy may help in stratifying patient outcome and monitoring for relapse. To identify potential plasma biomarkers, we utilised a liquid chromatography-tandem mass spectrometry-based proteomics approach to detect differentially-expressed proteins in serum from TH-MYCN mice. TH-MYCN mice carry multiple copies of the human MYCN oncogene in the germline and homozygous mice for the transgene develop neuroblastoma in a manner resembling the human disease. The abundance of plasma proteins was measured over the course of disease initiation and progression. A list of 86 candidate plasma biomarkers was generated. Pathway analysis identified significant association of these proteins with genes involved in the complement system. One candidate, complement C3 protein, was significantly enriched in the plasma of TH-MYCN+/+ mice at both 4 and 6weeks of age, and was found to be elevated in a cohort of human neuroblastoma plasma samples, compared to healthy subjects. In conclusion, we have demonstrated the suitability of the TH-MYCN+/+ mouse model of neuroblastoma for identification of novel disease biomarkers in humans, and have identified Complement C3 as a candidate plasma biomarker for measuring disease state in neuroblastoma patients. Biological significance: This study has utilised a unique murine model which develops neuroblastoma tumours that are biologically indistinguishable from human neuroblastoma. This animal model has effectively allowed the identification of plasma proteins which may serve as potential biomarkers of neuroblastoma. Furthermore, the label-free ion count quantitation technique which was used displays significant benefits as it is less labour intensive, feasible and accurate. We have been able to successfully validate this approach by confirming the differential abundance of two different plasma proteins. In addition, we have been able to confirm that the candidate biomarker Complement C3, is more abundant in the plasma of human neuroblastoma patient plasma samples when compared to healthy counterparts. Overall we have demonstrated that this approach can be potentially useful in the identification of biomarker candidates, and that further validation of the candidates may lead to the discovery of novel, clinically useful diagnostic tools in the detection of sub-clinical neuroblastoma.

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