Abstract
BackgroundThe clinical benefit of guaiac fecal occult blood tests (FOBT) is now well established for colorectal cancer screening. Growing evidence has demonstrated that epigenetic modifications and fecal microbiota changes, also known as dysbiosis, are associated with CRC pathogenesis and might be used as surrogate markers of CRC.Patients and MethodsWe performed a cross-sectional study that included all consecutive subjects that were referred (from 2003 to 2007) for screening colonoscopies. Prior to colonoscopy, effluents (fresh stools, sera-S and urine-U) were harvested and FOBTs performed. Methylation levels were measured in stools, S and U for 3 genes (Wif1, ALX-4, and Vimentin) selected from a panel of 63 genes; Kras mutations and seven dominant and subdominant bacterial populations in stools were quantified. Calibration was assessed with the Hosmer-Lemeshow chi-square, and discrimination was determined by calculating the C-statistic (Area Under Curve) and Net Reclassification Improvement index.ResultsThere were 247 individuals (mean age 60.8±12.4 years, 52% of males) in the study group, and 90 (36%) of these individuals were patients with advanced polyps or invasive adenocarcinomas. A multivariate model adjusted for age and FOBT led to a C-statistic of 0.83 [0.77–0.88]. After supplementary sequential (one-by-one) adjustment, Wif-1 methylation (S or U) and fecal microbiota dysbiosis led to increases of the C-statistic to 0.90 [0.84–0.94] (p = 0.02) and 0.81 [0.74–0.86] (p = 0.49), respectively. When adjusted jointly for FOBT and Wif-1 methylation or fecal microbiota dysbiosis, the increase of the C-statistic was even more significant (0.91 and 0.85, p<0.001 and p = 0.10, respectively).ConclusionThe detection of methylated Wif-1 in either S or U has a higher performance accuracy compared to guaiac FOBT for advanced colorectal neoplasia screening. Conversely, fecal microbiota dysbiosis detection was not more accurate. Blood and urine testing could be used in those individuals reluctant to undergo stool testing.
Highlights
Colorectal cancer (CRC) is a significant cause of morbidity and mortality in developed countries
A multivariate model adjusted for age and fecal occult blood tests (FOBT) led to a C-statistic of 0.83 [0.77–0.88]
The detection of methylated Wif-1 in either S or U has a higher performance accuracy compared to guaiac FOBT for advanced colorectal neoplasia screening
Summary
Colorectal cancer (CRC) is a significant cause of morbidity and mortality in developed countries. The screening colonoscopy, the ‘‘gold-standard method’’, flexible sigmoidoscopy, and computed tomography colonography have been shown to be effective for CRC screening by demonstrating a reduction in CRC incidence and mortality [3,4,5,6]. The guaiac fecal occult blood test (FOBT) has been shown to reduce CRC-related mortality in three randomized controlled trials and one population-based study [7,8,9,10]. The quantitative immunochemical FOBT has recently demonstrated a higher sensitivity in the detection of advanced neoplasias [13]. The clinical benefit of guaiac fecal occult blood tests (FOBT) is well established for colorectal cancer screening. Growing evidence has demonstrated that epigenetic modifications and fecal microbiota changes, known as dysbiosis, are associated with CRC pathogenesis and might be used as surrogate markers of CRC
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