Higher Levels of Lecithin Retinol Acyltransferase Hypermethylation May Correlate With Earlier Stage of Colorectal Cancer
Compared with normal colorectal mucosae, nearly half of colorectal tumors showed medium-to-high levels of lecithin retinol acyltransferase (LRAT) hypermethylation, according to the results of a study reported by Cheng et al in Medical Oncology. This finding was noted more frequent in earlier tumor stages than in later stages.
Previous clinical studies have demonstrated a connection between retinoids and colonocyte function—and with it the development of neoplasms of the colon. Vitamin A deficiency has been linked to colon cancer. In addition, reduced expression of retinol dehydrogenases has been associated with colonic adenomas and carcinomas. In addition, interest has also increased in the role LRAT plays in vitamin A metabolism and its relationship to neoplasms of the colon.
Previous analyses have detected a decrease in LRAT activity in various cancer cell lines and cancer tissues, including those of the prostate, breast, oral cavity, skin, bladder, and kidneys. Thus, Cheng and colleagues set forth to determine the function of LRAT in the development of colorectal cancer.
Study Details
The investigators analyzed LRAT hypermethylation status in 5 colorectal cancer cell lines, 167 colorectal tumors, and 69 adjacent normal colonic mucosae. Study data were obtained from patients at Memorial Sloan Kettering Cancer Center in New York who were treated for a sporadic colorectal neoplasm between 1992 and 2004. Primary tumors were located in the proximal colon, the distal colon, or the rectum. The median age of patients was 66 (range, 17–86 years).
Methylation levels at six CpG sites (where a cytosine nucleotide occurs next to a guanine nucleotide) located in an LRAT intronic region were averaged to determine the overall promoter methylation value. Hypermethylation was suspected when a sample’s overall methylation value was greater than one standard deviation of the mean of normal tissues’ overall promoter methylation values. This cutoff scored samples with 15% or more methylation in a promoter region.
Hypermethylation Levels Higher in Primary Colorectal Tumors
The investigators found that compared with normal colorectal mucosae, nearly half of the colorectal tumors showed medium-to-high levels of LRAT hypermethylation (P = .0025). It was also noted that the occurrence of hypermethylation was more common in earlier tumor stages (I/II) than in later stages (III/IV).
Also of interest was the finding that LRAT hypermethylation was identified in 12 of the 13 examined colorectal polyps, indicating that this phenomenon occurred early during the development of colorectal cancer. In addition, hypermethylation took place in nearly 22% of adjacent normal colonic mucosae and was seen more frequently in older and female patients with colorectal cancer. This presence of methylated loci in the adjacent normal-appearing tissues may imply that abnormal gene expression occurs not only within close proximity to the tumor margin but also possibly extends to the entire mucosal field.
Closing Thoughts
The investigators determined that LRAT promoter hypermethylation affects the modulation of LRAT gene expression and function. Because colorectal cancer patients with microsatellite instability tumors or early-stage microsatellite-stable tumors are known to have a better prognosis than patients with advanced microsatellite-stable tumors, a higher incidence of LRAT hypermethylation in microsatellite-instability tumors and early-stage colorectal cancer may correlate with better survival or more favorable clinical outcomes.
“Our study shows that LRAT promoter hypermethylation occurs frequently in [colorectal cancers]. Promoter hypermethylation resulting in gene silencing provides a plausible mechanism for the reduced LRAT expression observed in various human cancers,” they concluded.
Yu-Wei Cheng, PhD, of the Department of Laboratory Medicine, Cleveland Clinic, Cleveland, is the corresponding author of this article in Medical Oncology.
The study authors reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
