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Proc Natl Acad Sci U S A. 2019 Apr 10. pii: 201813212. doi: 10.1073/pnas.1813212116. [Epub ahead of print]

Conserved serum protein biomarkers associated with growing early colorectal adenomas.

Author information

1
Biotechnology Center, University of Wisconsin-Madison, Madison, WI 53706; ivancic@wisc.edu ppickhardt2@uwhealth.org mxr@medicine.wisc.edu msussman@wisc.edu dove@oncology.wisc.edu.
2
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706.
3
Biotechnology Center, University of Wisconsin-Madison, Madison, WI 53706.
4
Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792; ivancic@wisc.edu ppickhardt2@uwhealth.org mxr@medicine.wisc.edu msussman@wisc.edu dove@oncology.wisc.edu.
5
Department of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705.
6
Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792.
7
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705.
8
Department of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705; ivancic@wisc.edu ppickhardt2@uwhealth.org mxr@medicine.wisc.edu msussman@wisc.edu dove@oncology.wisc.edu.
9
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705; ivancic@wisc.edu ppickhardt2@uwhealth.org mxr@medicine.wisc.edu msussman@wisc.edu dove@oncology.wisc.edu.
10
Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706.

Abstract

A major challenge for the reduction of colon cancer is to detect patients carrying high-risk premalignant adenomas with minimally invasive testing. As one step, we have addressed the feasibility of detecting protein signals in the serum of patients carrying an adenoma as small as 6-9 mm in maximum linear dimension. Serum protein biomarkers, discovered in two animal models of early colonic adenomagenesis, were studied in patients using quantitative mass-spectrometric assays. One cohort included patients bearing adenomas known to be growing on the basis of longitudinal computed tomographic colonography. The other cohort, screened by optical colonoscopy, included both patients free of adenomas and patients bearing adenomas whose risk status was judged by histopathology. The markers F5, ITIH4, LRG1, and VTN were each elevated both in this patient study and in the studies of the Pirc rat model. The quantitative study in the Pirc rat model had demonstrated that the elevated level of each of these markers is correlated with the number of colonic adenomas. However, the levels of these markers in patients were not significantly correlated with the total adenoma volume. Postpolypectomy blood samples demonstrated that the elevated levels of these four conserved markers persisted after polypectomy. Two additional serum markers rapidly renormalized after polypectomy: growth-associated CRP levels were enhanced only with high-risk adenomas, while PI16 levels, not associated with growth, were reduced regardless of risk status. We discuss biological hypotheses to account for these observations, and ways for these signals to contribute to the prevention of colon cancer.

KEYWORDS:

longitudinal CT colonography; murine models; overdiagnosis; quantitative mass spectrometry; tumor volume

PMID:
30971492
DOI:
10.1073/pnas.1813212116
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Conflict of interest statement

Conflict of interest statement: P.J.P. is cofounder of VirtuoCTC, consultant for Bracco and Check-Cap, and shareholder of SHINE, Elucent, and Cellectar. M.M.I., P.J.P., M.R., M.R.S., and W.F.D. are inventors on patent application PCTUS2015065049 submitted by The Wisconsin Alumni Research Foundation that covers the quantitative proteomic analysis, animal model, and patient resource design described in this report. The other authors declare no potential conflicts of interest.

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