NDRG4 is a candidate tumor suppressor gene in colorectal cancer whose expression is frequently inactivated by promoter methylation. NDRG4 promoter methylation is a potential biomarker for the noninvasive detection of colorectal cancer in stool samples.

We have used a gene expression array-based strategy to identify the methylation of tissue factor pathway inhibitor 2 (TFPI2), a potential tumor suppressor gene, as a frequent event in human colorectal cancers (CRC). TFPI2 belongs to the recently described group of embryonic cell Polycomb group (PcG)-marked genes that may be predisposed to aberrant DNA methylation in early stages of colorectal carcinogenesis. Aberrant methylation of TFPI2 was detected in almost all CRC adenomas (97%, n = 56) and stages I to IV CRCs (99%, n = 115). We further explored the potential of TFPI2 as a biomarker for the early detection of CRC using stool DNA-based assays in patients with nonmetastatic CRC and average-risk noncancer controls who were candidates for screening. TFPI2 methylation was detected in stool DNA from stage I to III CRC patients with a sensitivity of 76% to 89% and a specificity of 79% to 93%. Detection of TFPI2 methylation in stool DNA may act as a useful adjunct to the noninvasive strategies for screening of CRCs in the future. [Cancer Res 2009;69(11):4691-9]

Purpose: The transcription factors GATA4 and GATA5 are involved in gastrointestinal development and are inactivated by promoter hypermethylation in colorectal cancer. Here, we evaluated GATA4/5 promoter methylation as potential biomarkers for noninvasive colorectal cancer detection, and investigated the role of GATA4/5 in colorectal cancer. Experimental Design: Promoter methylation of GATA4/5 was analyzed in colorectal tissue and fecal DNA from colorectal cancer patients and healthy controls using methylation-specific PCR. The potential function of GATA4/5 as tumor suppressors was studied by inducing GATA4/5 overexpression in human colorectal cancer cell lines. Results: GATA4/5 methylation was observed in 70% (63/90) and 79% (61/77) of colorectal carcinomas, respectively, and was independent of clinicopathologic features. Methylation frequencies in normal colon tissues from noncancerous controls were 6% (5 of 88, GATA4; P < 0.001) and 13% (13 of 100, GATA5; P < 0.001). GATA4/5 overexpression suppressed colony formation (P < 0.005), proliferation (P < 0.001), migration (P < 0.05), invasion (P < 0.05), and anchorage-independent growth (P < 0.0001) of colorectal cancer cells. Examination of GATA4 methylation in fecal DNA from two independent series of colorectal cancer patients and controls yielded a sensitivity of 71% [95% confidence interval (95% CI), 55-88%] and specificity of 84% (95% CI, 74^95%) for colorectal cancer detection in the training set, and a sensitivity of 51% (95% CI, 37^65%) and specificity of 93% (95% CI, 84-100%) in the validation set. Conclusions: Methylation of GATA4/5 is a common and specific event in colorectal carcinomas, and GATA4/5 exhibit tumor suppressive effects in colorectal cancer cells in vitro. GATA4 methylation in fecal DNA may be of interest for colorectal cancer detection.

In recent years, attention has focused on the biology and potential clinical importance of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). While it is generally well accepted that etiologically and clinically distinct subgroups exist in this disease, a precise definition of CIMP remains to be established. Here, we summarize existing literature that documents the prevalence of CIMP in CRC, with particular attention to the various methods and definitions used to classify a tumor as CIMP positive. Through a systematic review on both case-series and population based studies, we examined only original research articles reporting on sporadic CRC and/or adenomas in unselected cases. Forty-eight papers published between January 1999 and August 2011 met the inclusion criteria. We describe the use of multiple gene panels, marker threshold values, and laboratory techniques which results in a wide range in the prevalence of CIMP. Because there is no universal standard or consensus on quantifying the phenotype, establishing its true prevalence is a challenge. This bottleneck is becoming increasingly evident as molecular pathological epidemiology continues to offer possibilities for clear answers regarding environmental risk factors and disease trends. For the first time, large, unselected series of cases are available for analysis, but comparing populations and pooling data will remain a challenge unless a universal definition of CIMP and a consensus on analysis can be reached, and the primary cause of CIMP identified.

Given the current increase in colorectal cancer screening, information on performance of screening tests is needed, especially in groups with a presumed lower test performance. We compared test performance of immunologic fecal occult blood testing (FIT) and pseudosigmoidoscopy with colonoscopy for detection of advanced adenomas in an average risk screening population. In addition, we explored the influence of gender, age, and location on test performance. FIT was collected prior to colonoscopy with a 50 ng/mL cutoff point. FIT results and complete colonoscopy findings were available from 329 subjects (mean age: 54.6 AE 3.7 years, 58.4% women). Advanced adenomas were detected in 38 (11.6%) of 329 subjects. Sensitivity for advanced adenomas of FIT and sigmoidoscopy were 15.8% (95% CI: 6.0-31.3) and 73.7% (95% CI: 56.9-86.6), respectively. No sensitivity improvement was obtained using the combination of sigmoidoscopy and FIT. Mean fecal hemoglobin in FIT positives was significantly lower for participants with only proximal adenomas versus those with distal ones (P ¼ 0.008), for women versus men (P ¼ 0.023), and for younger (<55 years) versus older (!55 years) subjects (P ¼ 0.029). Sensitivities of FIT were 0.0% (95% CI: 0.0-30.9) in subjects with only proximal versus 21.4% (95% CI: 8.3-41.0) in those with distal nonadvanced adenomas; 5.3% (95% CI: 0.0-26.0) in women versus 26.3% (95% CI: 9.2-51.2) in men; 9.5% (95% CI: 1.2-30.4) in younger versus 23.5% (95% CI: 6.8-49.9) in older subjects. Sigmoidoscopy had a significantly higher sensitivity for advanced adenomas than FIT. A single FIT showed very low sensitivity, especially in subjects with only proximal nonadvanced adenomas, in women, and in younger subjects. This points to the existence of "low" FIT performance in subgroups and the need for more tailored screening strategies. Cancer Prev Res; 4(10); 1563-71. Ó2011 AACR.