Abstract
BackgroundThere is an increasing demand for accurate biomarkers for early non-invasive colorectal cancer detection. We employed a genome-scale marker discovery method to identify and verify candidate DNA methylation biomarkers for blood-based detection of colorectal cancer.Methodology/Principal FindingsWe used DNA methylation data from 711 colorectal tumors, 53 matched adjacent-normal colonic tissue samples, 286 healthy blood samples and 4,201 tumor samples of 15 different cancer types. DNA methylation data were generated by the Illumina Infinium HumanMethylation27 and the HumanMethylation450 platforms, which determine the methylation status of 27,578 and 482,421 CpG sites respectively. We first performed a multistep marker selection to identify candidate markers with high methylation across all colorectal tumors while harboring low methylation in healthy samples and other cancer types. We then used pre-therapeutic plasma and serum samples from 107 colorectal cancer patients and 98 controls without colorectal cancer, confirmed by colonoscopy, to verify candidate markers. We selected two markers for further evaluation: methylated THBD (THBD-M) and methylated C9orf50 (C9orf50-M). When tested on clinical plasma and serum samples these markers outperformed carcinoembryonic antigen (CEA) serum measurement and resulted in a high sensitive and specific test performance for early colorectal cancer detection.Conclusions/SignificanceOur systematic marker discovery and verification study for blood-based DNA methylation markers resulted in two novel colorectal cancer biomarkers, THBD-M and C9orf50-M. THBD-M in particular showed promising performance in clinical samples, justifying its further optimization and clinical testing.
Highlights
Colorectal cancer (CRC) is a common disease with an estimated 143,460 new cases in the USA in 2012 [1]
After removing potentially problematic probes, probe sequences that overlapped single nucleotide polymorphisms (SNPs) or repetitive elements, and probes that failed to perform in all samples, there were 23,049 HumanMethylation27 BeadChipH (HM27) probes and 367,254 HumanMethylation450 BeadChipH (HM450) probes
We excluded all probes with higher DNA methylation in normal colon tissue than in CRC and ranked the remaining probes based on the difference between healthy peripheral blood lymphocyte (PBL) and CRC tumor DNA methylation
Summary
Colorectal cancer (CRC) is a common disease with an estimated 143,460 new cases in the USA in 2012 [1]. It is clear that localized cancer (stage I/II) detected early is more amenable to curative therapy, offering superior prognosis [2,3]. Diagnostic methods that result in early detection of malignant or even premalignant disease could have considerable clinical benefits, reducing mortality and morbidity of patients with colorectal cancer. The measurement of serum carcinoembryonic antigen (CEA) has been suggested as a possible screening modality but it lacks sufficient sensitivity to detect CRC at an early stage, and its level is elevated in nonmalignant diseases (e.g. diverticulitis, gastritis, diabetes) [6]. There is an increasing demand for accurate biomarkers for early non-invasive colorectal cancer detection. We employed a genome-scale marker discovery method to identify and verify candidate DNA methylation biomarkers for blood-based detection of colorectal cancer
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