Aristaless-like homeobox-4 gene methylation is a potential marker for colorectal adenocarcinomas.
OBJECTIVE
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 Aristaless-like homeobox-4 (ALX4) gene that was highly methylated in colon adenomas and cancer was identified. Methylation of ALX4 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. ALX4 methylation was also analyzed in the serum of 30 patients with colon cancer.


RESULTS
ALX4 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) (P < .0001). In addition, ALX4 methylation was frequently observed in adenocarcinomas of the esophagus (12/14), stomach (11/15), and bile ducts (4/5) compared with all other cancers (P < .001). ALX4 gene methylation was also more frequently found in sera of patients with colon cancer compared with noncancer controls (P < .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, ALX4 is frequently methylated in adenocarcinomas of the gastrointestinal tract. ALX4 gene methylation in sera of patients with cancer may thus serve as a methylation-specific test for colon and other gastrointestinal cancers.
Ebert
Matthias P A
MP
Epigenomics Inc, Seattle, Washington; Fred Hutchinson Cancer Center, Seattle, Washington, USA. matthias.ebert@lrz.tum.de
Model
Fabian
F
Mooney
Suzanne
S
Hale
Kari
K
Lograsso
Joe
J
Tonnes-Priddy
Lori
L
Hoffmann
Juliane
J
Csepregi
Antal
A
Röcken
Christoph
C
Molnar
Bela
B
Schulz
Hans-Ulrich
HU
Malfertheiner
Peter
P
Lofton-Day
Catherine
C
D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D003111:Colonic Polyps / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D011230:Precancerous Conditions / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
C416676:ALX4 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors