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Blood-based protein biomarker signatures might be an alternative or supplement to existing methods for early detection of colorectal cancer (CRC) for population-based screening. The objective of this study was to derive a protein biomarker signature for early detection of CRC and its precursor advanced adenoma (AA). In a two-stage design, 270 protein markers were measured by liquid chromatography/multiple reaction monitoring/mass spectrometry in plasma samples of discovery and validation sets. In the discovery set consisting of 100 newly diagnosed CRC cases and 100 age- and sex-matched controls free of neoplasm at screening colonoscopy, the algorithms predicting the presence of early- or late-stage CRC were derived by Lasso regression and .632 + bootstrap. The prediction algorithms were then externally validated in an independent validation set consisting of participants of screening colonoscopy including 56 participants with CRC, 99 with AA and 99 controls without any colorectal neoplasms. Three different signatures for all-, early- and late-stage CRC consisting of five-, three- and eight-protein markers were obtained in the discovery set with areas under the curves (AUCs) after .632 + bootstrap adjustment of 0.85, 0.83 and 0.96, respectively. External validation in the representative screening population yielded AUCs of 0.79 (95% CI, 0.70-0.86), 0.79 (95% CI, 0.66-0.89) and 0.80 (95% CI, 0.70-0.89) for all-, early- and late-stage CRCs, respectively. The three-marker early-stage algorithm yielded an AUC of 0.65 (95% CI, 0.56-0.73) for detection of AA in the validation set. Although not yet competitive with available stool-based tests for CRC early detection, the identified proteins may contribute to the development of powerful blood-based tests for early detection of CRC and its precursors AAs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Blood-based protein biomarkers may be an attractive option for early detection of colorectal cancer (CRC). Here, we used a two-stage design to measure 275 protein markers by proximity extension assay (PEA), first in plasma samples of a discovery set consisting of 98 newly diagnosed CRC cases and 100 age- and gender-matched controls free of neoplasm at screening colonoscopy. An algorithm predicting the presence of early- or late-stage CRC was derived by least absolute shrinkage and selection operator regression with .632+ bootstrap method, and the algorithms were then validated using PEA again in an independent validation set consisting of participants of screening colonoscopy with and without CRC (n = 56 and 102, respectively). Three different signatures for all-, early-, and late-stage CRC consisting of 9, 12, and 11 protein markers were obtained in the discovery set with areas under the curves (AUCs) after .632 + bootstrap adjustment of 0.92, 0.91, and 0.96, respectively. External validation among participants of screening colonoscopy yielded AUCs of 0.76 [95% confidence interval (95% CI), 0.67-0.84], 0.75 (95% CI, 0.62-0.87), and 0.80 (95% CI, 0.68-0.89) for all-, early-, and late-stage CRC, respectively. Although the identified protein markers are not competitive with the best available stool tests, these proteins may contribute to the development of powerful blood-based tests for CRC early detection in the future., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Objectives: Most studies identifying inflammatory markers for early detection of colorectal cancer (CRC) were conducted using clinically manifest cases. We aimed to identify circulating inflammatory biomarkers for early detection of CRC and validate them in both a clinical setting and a true screening setting., Study Design and Setting: A total of 92 inflammatory proteins were quantified in baseline plasma samples from individuals clinically diagnosed with CRC and neoplasm-free controls matched on age and sex (training set). A multimarker panel was selected and evaluated in samples from another clinical setting (validation set C) and a screening setting (validation set S)., Results: In the training set (N = 330), a five-biomarker signature was selected that provided an area under curve (AUC) of 0.85 and 60.9% sensitivity to detect CRC at 90% specificity. When this algorithm was applied to validation set C (N = 318), the AUC (0.80) and sensitivity (49.5%) at 90% specificity for CRC diagnosis were only slightly lower than those in the training set. By contrast, the diagnostic performance of the algorithm in validation set S (N = 126) from a true screening setting was much poorer, with an AUC of 0.59 and a sensitivity of 28.6% at 90% specificity., Conclusions: An inflammation-related protein panel with apparently good diagnostic properties for CRC detection was identified and confirmed in an independent clinical validation set. However, the biomarker combination performed substantially worse in a validation sample from a true screening setting. Our results underline the importance of validation in screening settings subsequently to novel signature discovery for cancer early detection., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Despite evidence that inflammation and metabolism play a crucial role in colorectal carcinogenesis, there have been few studies on the association of inflammatory and metabolic protein biomarkers in various stages of colorectal carcinogenesis., Methods: Ninety-two inflammatory and metabolic biomarkers were measured in plasma samples of participants of screening colonoscopy. Markers identified to be significantly associated with the presence of advanced colorectal neoplasia (ACN) in a discovery set (n = 204) were validated in an independent replication set (n = 422). Adjusted associations with the presence of non-advanced adenomas (NAA), advanced precancerous lesions (APL) and colorectal cancer (CRC) were quantified by multiple logistic regression., Results: Out of the 92 inflammatory proteins, 72 markers were evaluable and 8 showed statistically significant associations with the odds of ACN after full adjustment for potential risk factors for CRC in the discovery set. One of these, fibroblast growth factor 21 (FGF-21), could be validated in the replication set. The multivariable-adjusted odds ratio (OR) reached 2.65 (95% CI, 1.50-4.81) for individuals with FGF-21 levels within the highest tertile, compared to those within the lowest tertile (P trend across tertiles = 0.001). Separate models revealed fully adjusted ORs for NAA, APL and CRC of 2.99 (95% CI, 1.45-6.58, P trend  = 0.005), 2.24 (95% CI, 1.18-4.44, P trend  = 0.021) and 3.92 (95% CI, 1.51-12.18, P trend  = 0.003), respectively., Conclusions: Circulating FGF-21 level is associated with increased risk of early and late stages of colorectal carcinogenesis, supporting a role of inflammation and metabolism at all stages of colorectal carcinogenesis, and suggesting potential use of this biomarker for risk stratification in CRC screening.

Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR)Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD) increase in IGF-I, ptrend = 0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3-Q1 = 1.38 [95% CI 1.01-1.89]; OR = 1.19 [95% CI 1.04-1.36] per 1-SD increase in IGF-I, ptrend = 0.01) but not with receptor-positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER- breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet = 0.03 for ER+/PR+ vs. ER-/PR- disease). Our data add to a global body of evidence indicating that higher circulating IGF-I levels may increase risk specifically of receptor-positive, but not receptor-negative, breast cancer diagnosed at 50 years or older., (© 2013 UICC.)