Abstract
BackgroundColorectal cancer (CRC) is one of the most common cancers in the western world. Screening is an efficient method of reducing cancer-related mortality. Molecular biomarkers for cancer in general and CRC in particular have been proposed, and hypermethylated DNA from stool or blood samples are already implemented as biomarkers for CRC screening.We aimed to evaluate the performance of proven hypermethylated DNA promoter regions as plasma based biomarkers for CRC detection.MethodsWe conducted a cross-sectional case-control study of 193 CRC patients and 102 colonoscopy-verified healthy controls. Using methylation specific polymerase chain reaction, we evaluated 30 DNA promoter regions previously found to be CRC specific. We used multivariable logistic regression with stepwise backwards selection, and subsequent leave-pair-out cross validation, to calculate the optimism corrected area under the receiver operating characteristics curve (AUC) for all stage as well as early stage CRC.ResultsNone of the individual DNA promoter regions provided an overall sensitivity above 30% at a reasonable specificity. However, seven hypermethylated promoter regions (ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, and VIM) along with the covariates sex and age yielded an optimism corrected AUC of 0.86 for all stage CRC and 0.85 for early stage CRC. Overall sensitivity for CRC detection was 90.7% at 72.5% specificity using a cut point value of 0.5.ConclusionsIndividual hypermethylated DNA promoter regions have limited value as CRC screening markers. However, a panel of seven hypermethylated promoter regions show great promise as a model for CRC detection.
Highlights
Colorectal cancer (CRC) is one of the most common cancers, reaching annual incidence rates of >1.3 million cases worldwide [1]
Ensuring survival of CRC patients relies on detection at early stages, which can be achieved through population-based screening [2,3]
Review of the CRC patients led to the exclusion of twelve patients: seven with benign disease or non-colorectal cancer, three did not have any residual cancer after endoscopic resection, one patient initially refused surgery, and one patient did not provide informed consent
Summary
Colorectal cancer (CRC) is one of the most common cancers, reaching annual incidence rates of >1.3 million cases worldwide [1]. The current screening program in Denmark includes an immunochemical faecal occult blood test (iFOBT) followed by a colonoscopy if iFOBT is positive.[3] patient adherence to current screening programs is limited by low completion rates with great differences between ethnic groups [4]. This necessitates the development of other methods for early CRC detection in order to ensure patient survival. Molecular biomarkers for cancer in general and CRC in particular have been proposed, and hypermethylated DNA from stool or blood samples are already implemented as biomarkers for CRC screening.
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