Evaluation of a 5-Marker Blood Test for Colorectal Cancer Early Detection in a Colorectal Cancer Screening Setting

Werner, Simone; Krause, Friedemann; Rolny, Vinzent; Strobl, Matthias; Morgenstern, David; Datz, Christian; Chen, Hongda; Brenner, Hermann

doi:10.1158/1078-0432.ccr-15-1268

Cited by 54 publications

(77 citation statements)

References 34 publications

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“…Moreover, FAPα combined with the three traditional biomarkers improved the sensitivity (41.5%) without compromising specificity (95.0%) for ESCC detection. Our data were consistent with those studies in which FAPα improved the diagnostic value of CRC [4–5]. These results showd the screen value of FAPα for ESCC, and demonstrated that the combination of FAPα and the three traditional biomarkers can detect about 40% ESCC.…”

Section: Discussionsupporting

confidence: 93%

“…Recently, circulating fibroblast activation protein α (FAPα) shows good specificity for colorectal cancer (CRC) diagnosis, and the combination of FAPα and other multiple markers all show high sensitivity for early detection of CRC [4–5]. Circulating FAPα levels were demonstrated significantly lower in cancer patients compared with healthy subjects and correlated inversely with survival in most types of cancer [6–9].…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the circulating level of fibroblast activation protein α for diagnosis of esophageal squamous cell carcinoma

Liao

Xing

et al. 2017

Oncotarget

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To evaluate whether circulating fibroblast activation protein α (FAPα) could serve as a biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), enzyme-linked immunosorbent assay (ELISA) was used to detect plasma FAPα in 556 participants including ESCC group, benign esophageal disease group, healthy controls and other cancer controls group. The levels of plasma FAPα were significantly decreased in ESCC patients (P < 0.001) and showed a positive correlation with HDL-C levels (R = 0.372, P < 0.001). The sensitivity and specificity of plasma FAPα were 56.1% and 85.6% based on the optimal cut-off (49.04 ng/ml, AUC = 0.714). The combination of FAPα and the traditional biomarkers (CEA, CYFR211 and SCCA) improved the sensitivity (41.5%) without compromising the specificity (95.0%). Contradictorily, the immunohistochemical staining revealed the overexpression of FAPα in stroma of ESCC tissues. So the source of soluble FAPα was further explored by qRT-PCR, Western blotting, ELISA and immunoprecipitation in fibroblast cell lines and mouse xenograft models. We found that the plasma FAPα was not correlated with the FAPα expressed in tumor, and the multi-organ might contribute to the circulating levels of FAPα including skeletal muscle, liver and bone marrow. These results indicated that the low plasma FAPα level might due to the systemic reaction to the presence of tumor and circulating FAPα level might be a potential indicator for diagnosing ESCC.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Evaluation of the circulating level of fibroblast activation protein α for diagnosis of esophageal squamous cell carcinoma

Liao

Xing

et al. 2017

Oncotarget

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“…if polyps)NoWerner et al (2016) [9]RetrospectiveCEAFerritin Seprase Osteoponti nAnti-p5336 CRC420 advanc ed adenom a, 1200 controlsSerum0.7844%90%NDYes (CEA sens 50%, spec 90%)Yes (early cancers were detected at least as well as late-stage)NoCEA + anti-p530.8558%90%Wang et al (2016) [61]ProspectiveCOL3A186 CRC21 enteritis, 3 polyps, 68 normalPlasmaEpithelial tissue0.920.97598.8%95.2%69.1%91.1%54.23 ng/m LYes (CEA: AUC 0.791, sens 70.2%, spec 73%)YesYes (mRNA)Rho et al (2016) [22]RetrospectiveBAG4 IL6ST** VWFEGFRBAG4 IL6ST VWFCD4460 CRC60 adenom as, 30 controlPlasma/Serum0.810.7940.9%42.44%90%NDNoNoYesOverholt et al (2016) [22]ProspectiveCA11-19131 CRC, 65 polyps, 182 benign disease, 103 controlsSerumND98%84%6.4 units/mLNoNoNoGezer et al (2015) [62]ProspectiveTrimethylations of lysine 9 on histone 3 (H3K9me3)Trimethylations of lysine 20 on histone 4 (H4K20me3)63 CRC40 cancer-freePlasmaNo significant difference between CRC and controls 0.715ND14.3%Yes95%NoNo…”

Section: Resultsmentioning

confidence: 99%

Systematic review of blood diagnostic markers in colorectal cancer

et al. 2018

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The purpose of this systematic review was to compare the diagnostic ability of blood markers for colorectal cancer (CRC). A systematic review of the literature for diagnostic blood markers for primary human colorectal cancer over the last 5 years was performed. The primary outcome was to assess the diagnostic ability of these markers in diagnosing colorectal cancer. The secondary outcome was to see whether the marker was compared to other markers. The tertiary outcome was to assess diagnostic ability in early versus late CRC, including stage IV disease. We identified 51 studies (29 prospective, 14 retrospective, and 8 meta-analyses). The markers were divided in broadly four groups: nucleic acids (RNA/DNA/messenger RNA/microRNAs), cytokines, antibodies, and proteins. The most promising circulating markers identified among the nucleid acids were NEAT_v2 non-coding RNA, SDC2 methylated DNA, and SEPT9 methylated DNA. The most promising cytokine to detect CRC was interleukin 8, and the most promising circulating proteins were CA11-19 glycoprotein and DC-SIGN/DC-SIGNR. Sensitivities of these markers for detecting primary colorectal carcinoma ranged from 70 to 98% and specificities from 84 to 98.7%. The best studied blood marker was SEPT9 methylated DNA, which showed great variability with sensitivities ranging from 48.2 to 95.6% and specificities from 80 to 98.9%, making its clinical applicability challenging. If combined with fecal immunochemical test (FIT), the sensitivity improved from 78 to 94% in detecting CRC. Methylated SEPT9, methylated SDC2, and -SIGN/DC-SIGNR protein had better sensitivity and specificity than CEA or CA 19-9. With the exception of SEPT9 which is currently being implemented as a screening test for CRC all other markers lacked reproducibility and standardization and were studied in relatively small population samples.

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“…Non-invasive tests could increase participation in CRC screening programs and interest in the identification of suitable biomarkers is growing [8], but only a few were validated in a screening setting: the most advanced blood test so far, based on the detection of cell-free methylated SEPT9 in plasma, achieved a sensitivity (specificity) of 48% (92%) for the detection of CRC [9]. The combination of two other markers, CEA and anti-TP53 antibody, also evaluated in the BLITZ study (albeit not using the same samples as in the current analysis), achieved a sensitivity (specificity) of 58% (90%) [15]. Stool tests represent another non-invasive alternative.…”

Section: Discussionmentioning

confidence: 83%

Epigenome-wide discovery and evaluation of leukocyte DNA methylation markers for the detection of colorectal cancer in a screening setting

Heiss

Brenner

2017

Clin Epigenet

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Background: Colorectal cancer (CRC) is the third most common cancer worldwide. If detected at an early stage, prognosis is good. Despite increasing evidence for the benefits of implemented screening programs, such as screening colonoscopy, compliance is rather low. Hence there is demand for non-invasive tests for the early detection of CRC with high acceptance in population-wide screening. The objective of this study was to identify and evaluate leukocyte DNA methylation patterns as a potential biomarker for early detection of CRC. Methods: Blood samples of patients scheduled for a screening colonoscopy were collected before the procedure. Additionally, blood samples from CRC cases recruited in a clinical setting were collected. DNA was extracted from leukocytes, and DNA methylation was measured with the Infinium 450K BeadChip. In total, 46 CRC cases and 140 controls from the screening setting and 93 CRC cases from the clinical setting were measured. Results: An epigenome-wide discovery revealed two CpG sites in the promoter region of KIAA1549L that were significantly differentially methylated between cases and controls. A third marker in the body region of BCL2 was discovered in a candidate approach testing biomarkers reported in the literature. Logistic regression models built on these three markers yielded an optimism-corrected c-statistic of 0.69 in the screening setting and 0.73 in the clinical setting. Conclusions: Although diagnostic performance of the DNA methylation signature identified in this first epigenomewide association study of leukocyte DNA methylation with CRC in a screening setting is not competitive with established screening tests, the identified markers may contribute to multimarker panels for early detection of CRC.

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Evaluation of a 5-Marker Blood Test for Colorectal Cancer Early Detection in a Colorectal Cancer Screening Setting

Cited by 54 publications

References 34 publications

Evaluation of the circulating level of fibroblast activation protein α for diagnosis of esophageal squamous cell carcinoma

Evaluation of the circulating level of fibroblast activation protein α for diagnosis of esophageal squamous cell carcinoma

Systematic review of blood diagnostic markers in colorectal cancer

Epigenome-wide discovery and evaluation of leukocyte DNA methylation markers for the detection of colorectal cancer in a screening setting

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