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Background: Colorectal cancer is one of the major causes of cancer mortality world-wide. Prevention would improve if at-risk subjects could be identified. The aim of this study was to characterise plasma protein biomarkers associated with the risk of colorectal cancer in samples collected prospectively, before the disease diagnosis., Methods: After an exploratory study on the comprehensive plasma proteome analysis by liquid chromatography-tandem mass spectrometry from ten colorectal cancer cases enrolled at diagnosis, and ten matched controls (Phase 1), a similar preliminary study was performed on prospective plasma samples from ten colorectal cancer cases, enrolled years before disease development, and ten matched controls identified in a nested case-control study within the Florence cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) study (Phase 2); in Phase 3 the validation of the candidate biomarkers by targeted proteomics on 48 colorectal cancer cases and 48 matched controls from the Florence-EPIC cohort, and the evaluation of the disease risk were performed., Results: Systems biology tools indicated that both in the Phase 1 and Phase 2 studies circulating protein levels differing in cases more than 1.5 times from controls, were involved in inflammation and/or immune response. Eight proteins including apolipoprotein C-II, complement C4-B, complement component C9, clusterin, alpha-2-HS-glycoprotein, mannan-binding lectin serine-protease, mannose-binding protein C, and N-acetylmuramoyl-L-alanine amidase were selected as promising candidate biomarkers. Targeted proteomics of the selected proteins in the EPIC samples showed significantly higher clusterin levels in cases than controls, but only in men (mean ± SD, 1.98 ± 0.46 and 1.61 ± 0.43 nmol/mL respectively, Mann-Whitney U, two-tailed P = 0.0173). The remaining proteins were unchanged. Using multivariate logistic models a significant positive association emerged for clusterin, with an 80% increase in the colorectal cancer risk with protein's unit increase, but only in men., Conclusions: The results show that plasma proteins can be altered years before colorectal cancer detection. The high circulating clusterin in pre-diagnostic samples suggests this biomarker can improve the identification of people at risk of colorectal cancer and might help in designing preventive interventions.

Clusterin/apolipoprotein J (CLU) is a conserved, ubiquitously expressed secreted glycoprotein that has been implicated in several physiological processes and was found to accumulate in many severe physiological disturbances. We have previously shown that the CLU gene and protein are upregulated during replicative senescence, stress-induced premature senescence, in vivo aging, and in several age-related diseases. In this study we have examined the CLU gene relationship to human longevity. We recruited and further analyzed 96 blood samples from Italian and Greek healthy donors of different ages, including 49 centenarians. We found that although the CLU gene expression levels increase during aging, in the centenarians' samples CLU levels were lower than those found in old donors. We then investigated the possible existence of a genetic polymorphism related to longevity at the CLU structural locus. A neutral noncoding sequence variant was detected 35 nucleotides upstream from exon 6, which does not correlate, however, with the age of the donor. We conclude that CLU gene accumulation during in vivo aging does not directly relate to chronological age, but rather indicates increased levels of organismal stress due to a progressive failure of homeostasis and/or to prolonged exposure to a stressful environment.