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The structural integrity of mitochondrial DNA reveals new molecular perspectives for early diagnosis of colorectal cancer

ABSTRACT: Interventions: Group 1: The project aims to: Statistically compare the fragment length of cell-free DNA in the blood plasma of 80 patients with a confirmed diagnosis of colorectal carcinoma in stages I-IV with the cfDNA fragment lengths of 50 healthy subjects. For this purpose, residual amounts of blood plasma samples are used, which are collected anyway as part of theroutine examinations. Cell-free DNA was isolated from the blood plasma and the fragment lengths are measured using qPCR. The project ends with the publication of the data. Group 2: Statistically compare the fragment length of cell-free DNA in the blood plasma of 50 healthy subjects with 80 patients with a confirmed diagnosis of colorectal carcinoma in stages I-IV. The plasma samples from healthy volunteers were purchased (Central Biohub GmbH). Primary outcome(s): The aim of this study is: 1) to analyze total cfDNA concentration in CRC patients with different histopathological stages (UICC I-IV). 2) to address the question whether the integrity index of cfDNA increases in CRC patients as a result of elevated necrotic degradation processes. Therefore, we intended to quantify short and long fragments of cfDNA via qPCR independent from total cfDNA levels by using equal template concentrations for CRC patients and healthy individuals. This approach may help to understand whether previously described diagnostic markers are either increased, decreased or unaltered in blood plasma of CRC patients compared to healthy individuals. Study Design: Allocation: ; Masking: ; Control: ; Assignment: ; Study design purpose: basic science

DISEASE(S): Malignant Neoplasm Of Rectum,Malignant Neoplasm Of Colon

PROVIDER: 2754663 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Background: Colorectal cancer (CRC) is one of the major causes of cancer-related death worldwide. Although commercial biomarkers of CRC are currently available, they are still lacking in terms of sensitivity and specificity; thus, searching for reliable blood-based biomarkers are important for the primary screening of CRC. Methods: Plasma samples of patients with non-metastatic (NM) and metastatic (M) CRC and healthy controls were fractionated using MARS-14 immunoaffinity chromatography. The flow-through and elute fractions representing low- and high-abundant proteins, respectively, were analyzed by label-free quantitative proteomics mass spectrometry. The functional analysis of the proteins with greater than 1.5-fold differential expression level between the CRC and the healthy control groups were analyzed for their biological processes and molecular functions. In addition, the levels of plasma proteins showing large alterations in CRC patients were confirmed by immunoblotting using two independent cohorts. Moreover, receiver operating characteristic (ROC) curve analysis was performed for individual and combinations of biomarker candidates so as to evaluate the diagnostic performance of biomarker candidates. Results: From 163 refined identifications, five proteins were up-regulated and two proteins were down-regulated in NM-CRC while eight proteins were up-regulated and three proteins were down-regulated in M-CRC, respectively. Altered plasma proteins in NM-CRC were mainly involved in complement activation, while those in M-CRC were clustered in acute-phase response, complement activation, and inflammatory response. Results from the study- and validation-cohorts indicate that the levels of LRG, C9, AGP1, and A1AT were statistically increased, while FN level was statistically decreased in CRC patients compared to healthy controls, with most alterations found in a metastatic stage-dependent manner. ROC analysis revealed that FN exhibited the best diagnostic performance to discriminate CRC patients and healthy controls while AGP1 showed the best discrimination between the disease stages in both cohorts. The combined biomarker candidates, FN+A1AT+AGP1, exhibited perfect discriminatory power to discriminate between the CRC population and healthy controls whereas LRG+A1AT+AGP1 was likely to be the best panel to discriminate the metastatic stages in both cohorts. Conclusions: This study identified and quantified distinct plasma proteome profiles of CRC patients. Selected CRC biomarker candidates including FN, LRG, C9, A1AT, and AGP1 may be further applied for screening larger cohorts.

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The structural integrity of mitochondrial DNA reveals new molecular perspectives for early diagnosis of colorectal cancer

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