Mutant proteins as cancer-specific biomarkers

Qing Wang, Raghothama Chaerkady, Jian Wu, Hee Jung Hwang, Nick Papadopoulos, Levy Kopelovich, Anirban Maitra, Hanno Matthaei, James R. Eshleman, Ralph H. Hruban, Kenneth W. Kinzler, Akhilesh Pandey, Bert Vogelstein

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

Cancer biomarkers are currently the subject of intense research because of their potential utility for diagnosis, prognosis, and targeted therapy. In theory, the gene products resulting from somatic mutations are the ultimate protein biomarkers, being not simply associated with tumors but actually responsible for tumor-igenesis. We show here that the altered protein products resulting from somatic mutations can be identified directly and quantified by mass spectrometry. The peptides expressed from normal and mutant alleles were detected by selected reaction monitoring (SRM) of their product ions using a triple-quadrupole mass spectrometer. As a prototypical example of this approach, we demonstrated that it is possible to quantify the number and fraction of mutant Ras protein present in cancer cell lines. There were an average of 1.3 million molecules of Ras protein per cell, and the ratio of mutant to normal Ras proteins ranged from 0.49 to 5.6. Similarly, we found that mutant Ras proteins could be detected and quantified in clinical specimens such as colorectal and pancreatic tumor tissues as well as in premalignant pancreatic cyst fluids. In addition to answering basic questions about the relative levels of genetically abnormal proteins in tumors, this approach could prove useful for diagnostic applications.

Original languageEnglish (US)
Pages (from-to)2444-2449
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number6
DOIs
StatePublished - Feb 8 2011

Keywords

  • Companion diagnostics
  • Genetic diagnosis
  • Genetics
  • Pancreatic cancer
  • Proteomics

ASJC Scopus subject areas

  • General

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    Wang, Q., Chaerkady, R., Wu, J., Hwang, H. J., Papadopoulos, N., Kopelovich, L., Maitra, A., Matthaei, H., Eshleman, J. R., Hruban, R. H., Kinzler, K. W., Pandey, A., & Vogelstein, B. (2011). Mutant proteins as cancer-specific biomarkers. Proceedings of the National Academy of Sciences of the United States of America, 108(6), 2444-2449. https://doi.org/10.1073/pnas.1019203108