Abstract
BackgroundAlthough the potential of biomarkers to aid in early detection of colorectal cancer (CRC) is recognized and numerous biomarker candidates have been reported in the literature, to date only few molecular markers have been approved for daily clinical use.MethodsIn order to improve the translation of biomarkers from the bench to clinical practice we initiated a biomarker study focusing on a novel technique, the proximity extension assay, with multiplexing capability and the possible additive effect obtained from biomarker panels. We performed a screening of 74 different biomarkers in plasma derived from a case–control sample set consisting of symptomatic individuals representing CRC patients, patients with adenoma, patients with non-neoplastic large bowel diseases and healthy individuals.ResultsAfter statistical evaluation we found 12 significant indicators of CRC and the receiver operating characteristic (ROC) curve of Carcinoembryonic antigen (CEA), Transferrin Receptor-1 (TFRC), Macrophage migration inhibitory factor (MIF), Osteopontin (OPN/SPP1) and cancer antigen 242 (CA242) showed additive effect. This biomarker panel identified CRC patients with a sensitivity of 56% at 90% specificity and thus the performance is sufficiently high to further investigate this combination of five proteins as serological biomarkers for detection of CRC. Furthermore, when applying the indicators to identify early-stage CRC a combination of CEA, TFRC and CA242 resulted in a ROC curve with an area under the curve of 0.861.ConclusionsFive plasma protein biomarkers were found to be potential CRC discriminators and three of these were additionally found to be discriminators of early-stage CRC. These explorative data in symptomatic individuals demonstrates the feasibility of the multiplex proximity extension assay for screening of potential serological protein biomarkers and warrants independent analyses in a larger sample cohort, including asymptomatic individuals, to further validate the performances of our CRC biomarker panel.
Highlights
Colorectal cancer (CRC) accounts for 608,700 deaths per year worldwide [1] which makes it one of the most common causes of cancer related deaths
We addressed the clinical needs for a blood-based test by initiating a protein biomarker study evaluating 74 different protein biomarkers in plasma samples from case–control patient material consisting of symptomatic individuals represented by colorectal cancer (CRC) patients, adenoma patients, patients with non-neoplastic large bowel diseases and healthy individuals
Low sample consumption and good assay performance in general is needed in order to facilitate high quality biomarker studies. We addressed these technical issues by applying the novel proximity extension assay (PEA) which is an improved version of a biomarker discovery tool with assay performance superior to the related Proximity Ligation Assay (PLA) in plasma samples [19]
Summary
Colorectal cancer (CRC) accounts for 608,700 deaths per year worldwide [1] which makes it one of the most common causes of cancer related deaths. Randomized clinical trials have demonstrated the value of population-based screening to reduce CRC-related mortality. Modalities as the Faecal Occult Blood Test (FOBT) and stool DNA (sDNA) tests are presently the only approved non-invasive screening tests available for detection of CRC in asymptomatic individuals. The performances of these tests have varied [4,5,6] and there is an immense problem with compliance [7,8]. One potential serological CRC screening test is the Septin 9 (SEPT9) methylated DNA test which has demonstrated good test performance in a prospective screening study including nearly 8,000 asymptomatic individuals. The potential of biomarkers to aid in early detection of colorectal cancer (CRC) is recognized and numerous biomarker candidates have been reported in the literature, to date only few molecular markers have been approved for daily clinical use
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