Title: Aristaless-like Homeobox-4 Gene Methylation Is a Potential Marker for Colorectal Adenocarcinomas
Abstract: Background & Aims: The identification of novel genetic and epigenetic markers indicative of changes in the pathogenesis of colon cancer, along with easier-to-use, more sensitive assay methods, may improve the detection, treatment, and overall prognosis of this malignancy. Methods: Using methylation-specific arbitrarily primed polymerase chain reaction, a fragment of the <i>Aristaless-like homeobox-4</i> (<i>ALX4</i>) gene that was highly methylated in colon adenomas and cancer was identified. Methylation of <i>ALX4</i> was analyzed in colorectal adenomas and cancers, in the liver metastases of patients with colorectal cancer, and in 61 other neoplasias, including gastric, esophageal, and hepatocellular cancer and cholangiocarcinoma. <i>ALX4</i> methylation was also analyzed in the serum of 30 patients with colon cancer. Results: <i>ALX4</i> gene methylation was confirmed in colon adenomas (11/13) and more frequently present in primary colorectal cancers (30/47) compared with the normal colon mucosa (0/21) (<i>P</i> < .0001). In addition, <i>ALX4</i> methylation was frequently observed in adenocarcinomas of the esophagus (12/14), stomach (11/15), and bile ducts (4/5) compared with all other cancers (<i>P</i> < .001). <i>ALX4</i> gene methylation was also more frequently found in sera of patients with colon cancer compared with noncancer controls (<i>P</i> < .0001). Using a cutoff of 41.4 pg/mL, sensitivity and specificity were 83.3% and 70%, respectively. Conclusions: Apart from colon adenomas and primary and metastatic colorectal cancers, <i>ALX4</i> is frequently methylated in adenocarcinomas of the gastrointestinal tract. <i>ALX4</i> gene methylation in sera of patients with cancer may thus serve as a methylation-specific test for colon and other gastrointestinal cancers.