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Circulating Tumor DNA Methylation Profiles May Aid in Colorectal Cancer Early Diagnosis, Prognosis

NEW YORK – The methylation profiles of circulating tumor DNA may help diagnose colorectal cancer as well as predict patient prognosis, findings that may form the basis of a new cancer test.

Early detection of colorectal cancer helps improve patients' survival, but colonoscopy-based screening is invasive, time-consuming, and expensive, all of which may adversely influence patient compliance.

Researchers led by Sun-Yat Sen University Cancer Center's Rui-hua Xu analyzed cell-free DNA to find that methylation patterns specific to colorectal cancer as a less invasive way of assessing colorectal cancer. As they reported this week in Science Translational Medicine, the researchers found that these patterns could be used to distinguish between individuals with and without colorectal cancer as well as between colorectal cancer patients with better or worse survival. Additionally, one methylation marker could detect colorectal cancer within a general population cohort with high sensitivity and specificity.

"Collectively, our findings demonstrated the use of cfDNA methylation markers for diagnosis, prognostication, and surveillance of CRC, with the potential to be used for early detection of asymptomatic patients with CRC," Xu and his colleagues wrote in their paper.

Irvine, California-based company Laboratory for Advanced Medicine, which focuses on developing liquid biopsy tests for cancer, is commercializing the test. According to a LAM spokesperson, this work is contributing to the development of its next commercial cancer test.

Xu and his colleagues compared methylation profiles for 459 colorectal cancer tumor samples generated by The Cancer Genome Atlas and 754 normal samples from a previous methylation study of aging, which they split into training and validation sets. The researchers homed in on nine markers that differed between the groups and used them to construct a diagnostic score for colorectal cancer. The resulting "cd-score" had high sensitivity — nearly 88 percent — and specificity — almost 90 percent — to distinguish colorectal cancer from controls.

Additionally, cd-scores were higher in pre-treatment patients than post-treatment patients; were higher among patients with detectable residual tumor after treatment; were higher after relapse; and were correlated with tumor stage. This suggested to the researchers that this score could detect residual tumor, evaluate whether a treatment is effective, and be used to screen for recurrences.

The researchers also constructed a prognostic prediction model, dubbed "cp-score," that combines cell-free methylation analysis with clinical and demographic features, such as tumor stage and site and patient age and gender. This cp-score could separate the patient cohort into a high- and a low-risk group with significantly different survival times and was highly correlated with risk of death. They generated a nomogram that includes cp-score, serum carcinoembryonic antigen concentration, tumor stage, and primary tumor location, all of which are independent predictive factors for overall patient survival.

One of the markers from within the cd-score, cg10673833, had a high diagnostic efficiency, the researchers noted, adding that its methylation changed as patients underwent treatment. This suggested that it could serve as a marker of colorectal cancer and precancerous lesions among individuals at a high risk of developing them. 

In a cohort of 1,493 individuals at high risk of colorectal cancer, cg10673833 methylation profiling identified 19 of the 21 individuals in the group with colorectal cancer and seven of the eight individuals with colorectal cancer in situ, a sensitivity of 89.7 percent and specificity of 86.8 percent. The sensitivity of the test was lower, 33.3 percent, for advanced precancerous lesions, but still higher than other reported cell-free DNA methylation markers for colorectal cancer.

This, the researchers noted, suggests that the marker could be an effective, noninvasive screening tool for colorectal cancer.

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