Abstract
Colorectal cancer (CRC) is one of the most prevalent and lethal malignancies. Especially for early stage CRC, prognostic molecular markers are needed to guide therapy. In this study, we first extracted total proteomes from matched pairs of fresh cancer and benign mucosal tissues from 22 CRC patients. Global proteomic profiling with Fourier transform liquid chromatography-mass spectrometry sequencing and label free quantitation uncovered that P4HA1 (prolyl 4-hydroxylase alpha 1) was overexpressed in CRC relative to benign colonic mucosa. We then investigated expression by immunohistochemical staining with P4HA1-specific antibodies using CRC tissue microarrays. Independent validation cohorts of 599 cases of early stage CRC and 91 cases of late stage CRC were examined. Multivariate and univariate survival analyses revealed that high expression of P4HA1 protein was an independent poor prognostic marker for patients with early stage CRC, especially of the microsatellite stable subtype. Our study provides strong support for P4HA1 as a predictive protein marker for precision diagnostics, therapeutic decision-making, and drug development for early stage colorectal cancer and demonstrates the utility of proteomic profiling to identify novel protein biomarkers.
Highlights
Colorectal cancer (CRC) is one of the most prevalent malignant tumors and the third leading cause of cancer deaths worldwide
Combining results from 712 patients, our study shows that collagen prolyl 4-hydroxylase alpha 1 (P4HA1) protein expression robustly risk-stratifies early stage CRC
To discover potential biomarkers for CRC, our first goal was to identify proteins that are differentially expressed in tumor tissue, those that are over-expressed in tumors relative to benign colonic mucosa
Summary
Colorectal cancer (CRC) is one of the most prevalent malignant tumors and the third leading cause of cancer deaths worldwide. Risk assessment at early stage is challenging because of a lack of reliable prognostic molecular biomarkers. Morphological features such as poorly differentiated histology, lymphovascular invasion, bowel obstruction, perineural invasion, localized perforation, and positive margins have been reported to worsen the prognosis of stage II CRC [4,5,6]. Molecular biomarkers with more precise prognostic value, preferably www.oncotarget.com with an underlying functional pathophysiologic rationale, are needed, as such markers would enable us to better stratify risk of recurrence in resected early stage CRC after resection and more accurately select patients for adjuvant therapy, while avoiding overtreatment in lowrisk early stage CRC
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