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Oncotarget | Prolyl 4-hydroxylase alpha 1 protein expression risk-stratifies early stage colorectal cancer


Oncotarget Volume 11, Issue 8 reported 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.

Dr. Michael H. Roehrl from the Department of Pathology, Memorial Sloan Kettering Cancer Center as well as the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center said, "Colorectal cancer (CRC) is one of the most prevalent malignant tumors and the third leading cause of cancer deaths worldwide."

"Colorectal cancer (CRC) is one of the most prevalent malignant tumors and the third leading cause of cancer deaths worldwide"

- Dr. Michael H. Roehrl, Department of Pathology, Memorial Sloan Kettering Cancer Center & Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center

However, molecular biomarkers with more precise prognostic value, preferably with an underlying functional pathophysiologic rationale, are needed, as such markers would enable the scientists 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 low-risk early-stage CRC.

Proteomics with latest-generation liquid chromatography-mass spectrometry can detect 5,000 - 10,000 proteins in one shotgun sequencing event, and such powerful and sensitive technology may enable the researchers to discover prognostic protein biomarkers for early-stage CRC that previous genomic and transcriptomic analyses would have missed.

Combining results from 712 patients, their study shows that collagen prolyl 4-hydroxylase alpha 1 protein expression robustly risk-stratifies early-stage CRC.

Figure 1: Mass spectrometric proteomics of CRC and global protein domain enrichment analysis. (A) Volcano plot of relative abundances of proteins from CRC relative vs. benign colonic mucosa as measured by mass spectrometry in matched samples from 22 patients. Among a total of 2,949 proteins displayed in the plot, we found 730 significantly differentially expressed proteins including 197 (red) up- and 533 (blue) down-regulated proteins. The hyperbolic solid lines show the false discovery rate frontier (FDR) set to 0.01. The x-axis shows the log2 of the fold change (FC) of protein abundance (ratio of cancer to benign mucosa). The y-axis shows the negative log10 of the t-test p value for a particular protein (dot in the volcano plot). (B) Global protein domain enrichment analysis of CRC up-regulated proteins using the Simple Modular Architecture Research Tool (SMART).

The discovery of P4HA1 outcome stratification in early-stage CRC and, in particular, its MSS subtype, may provide an avenue for early-stage CRC risk prognosis and thus improve cancer treatment outcomes by tailoring follow-up frequency and adjuvant therapy intensity.

The Roehrl Research Team concluded, in their Oncotarget Research Paper, that early-stage CRC presents frequent challenges in clinical patient management in that it is currently impossible to predict which patients will have aggressive disease and thus benefit the most from intensive adjuvant chemotherapy vs. those patients who will have less aggressive disease and benefit from surgery alone.

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DOI - https://doi.org/10.18632/oncotarget.27491

Full text - https://www.oncotarget.com/article/27491/text/

Correspondence to - Leny Toma - roehrlm@mskcc.org

Keywords - P4HA1, colorectal cancer, biomarker, prognosis, pathology

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