Urinary Polyamine Biomarker Panels with Machine-Learning Differentiated Colorectal Cancers, Benign Disease, and Healthy Controls.

Tetsushi Nakajima,Masahiro Sugimoto,Akihiko Tsuchida,Kenji Katsumata,Kana Hiwatari,Ryoko Soya,Tomoyoshi Soga,Masayo Mori,Masanobu Enomoto,Hiroshi Kuwabara,Tetsuo Ishizaki,Masaru Tomita

doi:10.3390/ijms19030756

Abstract

Colorectal cancer (CRC) is one of the most daunting diseases due to its increasing worldwide prevalence, which requires imperative development of minimally or non-invasive screening tests. Urinary polyamines have been reported as potential markers to detect CRC, and an accurate pattern recognition to differentiate CRC with early stage cases from healthy controls are needed. Here, we utilized liquid chromatography triple quadrupole mass spectrometry to profile seven kinds of polyamines, such as spermine and spermidine with their acetylated forms. Urinary samples from 201 CRCs and 31 non-CRCs revealed the N1,N12-diacetylspermine showing the highest area under the receiver operating characteristic curve (AUC), 0.794 (the 95% confidence interval (CI): 0.704–0.885, p < 0.0001), to differentiate CRC from the benign and healthy controls. Overall, 59 samples were analyzed to evaluate the reproducibility of quantified concentrations, acquired by collecting three times on three days each from each healthy control. We confirmed the stability of the observed quantified values. A machine learning method using combinations of polyamines showed a higher AUC value of 0.961 (95% CI: 0.937–0.984, p < 0.0001). Computational validations confirmed the generalization ability of the models. Taken together, polyamines and a machine-learning method showed potential as a screening tool of CRC.

Highlights

Colorectal cancer (CRC) is the second and third most frequently diagnosed cancer among males and females, respectively, both in the USA [1] and worldwide in 2012
Only N1,N12-acetylspermine and N1,N8-acetylspermidine showed a high area under the receiver operating characteristic (ROC) curves (AUC), allowing for discrimination of CRC from healthy controls; AUC = 0.794 (Figure 2b,c) and AUC = 0.664, respectively
This study aimed to discriminate CRC from the other conditions by using urinary metabolites quantified by LC-QqQMS to profile the seven kinds of polyamines

Summary

Introduction

Colorectal cancer (CRC) is the second and third most frequently diagnosed cancer among males and females, respectively, both in the USA [1] and worldwide in 2012. Tumor markers—such as serum carcinoembryonic antigen (CEA), CA19-9, and CA15-3—have been used to identify patients with CRC, but more accurate screening markers need to be developed. The development of screening biomarkers with higher sensitivity and specificity are still necessary. The naturally-occurring polyamines, spermidine and spermine, and their precursors, diamine and putrescine, are aliphatic polycations which are ubiquitously observed in mammalian cells. 2l0e18i,n19,txhe proliferation and differentiation of prokaryotic and normal oefu1k4 aryotic cells is well established [1] Polyamines, such as spermidine and spermine, are produced in almost all cTehllesnbatuutraallrye-opccaurrtriicnuglaprollyyahmiignhesl,yspperromdiduicneedanidn srpaeprmidinlye, ganrodwthienirgpcreecllusr.sorAs,rgdiianmininee, one of the amiannod pacuitdress,ciinse,caornevaleiprtheadtictpooolyrcnaittiohnisnwe hbiychaarrge iunbaiqsueit(oEuCsly3o.5b.s3e.r1v)e,dainndmaomrnmitahliainneceilsls.cTahtaeilryzed by ornithinewesesdlelneetcsiaatalrbbrloioslexheyindla[ts1he]e.

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