Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 6, Pages 2444-2449Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1019203108
Keywords
genetics; proteomics; pancreatic cancer; genetic diagnosis; companion diagnostics
Categories
Funding
- Lustgarten Foundation for Pancreatic Cancer Research, National Cancer Institute [NO1 CN-43302]
- Department of Defense [W81XWH-06-1-0428]
- Sol Goldman Center for Pancreatic Cancer Research
- Virginia and D. K. Ludwig Fund for Cancer Research
- Michael Rolfe Foundation
- Joseph L. Rabinowitz Fund for Pancreatic Cancer Research
- National Institutes of Health [CA62924, RR020839, CA130938, CA57345]
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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 tumorigenesis. 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.
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