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Methylation Profiles, Gene Signatures Help Predict Colon Cancer Recurrence, Survival

NEW YORK (GenomeWeb News) – Two new papers suggest methylation status and gene expression changes may help predict colon cancer survival and recurrence.
In a paper appearing in the advanced online edition of the Journal of the National Cancer Institute last night, an international team of researchers analyzed the methylation patterns in colon cancer samples taken from nearly 650 individuals. Their results suggest that decreased methylation in regions of the genome called long interspersed nucleotide element-1, or LINE-1, elements is associated with poor survival outcomes.
“[T]he results from this large prospective cohort study suggest that genome-wide DNA hypomethylation as measured in LINE-1 is independently associated with poor survival among patients with colon cancer,” lead author Shuji Ogino, a pathology researcher at the Dana-Farber Cancer Institute, and his colleagues wrote.
Colorectal cancer is the second most common cause of cancer death in the US. This year, it’s estimated that nearly 150,000 Americans will be diagnosed with the disease. In general, colon cancer prognoses are based on clinical staging, with roughly 40 percent of cases diagnosed in early or localized stages.
Patients with stage I and II colon cancer are often considered cured following surgery. Nevertheless, some 15 to 20 percent of these individuals eventually have recurrence of the disease. Consequently, researchers are interested in defining the molecular changes associated with recurrence and decreased survival.
For their part, Ogino and his team focused on DNA methylation, an epigenetic mechanism that’s involved in everything from imprinting to X-chromosome inactivation. Some studies have also suggested that decreased genome-wide methylation increases genomic instability.
Because the methylation of LINE-1 elements is thought to provide clues about global methylation patterns, Ogino and his team quantified LINE-1 methylation in 643 colon cancer samples collected through the Nurses’ Health Study and the Health Professionals Follow-up Study between 1976 and 2002. The team followed surviving individuals until the end of June 2006.
Using bisulfite treatment, real-time PCR, and pyrosequencing, the researchers quantified LINE-1 element methylation levels and looked at the relationship between methylation and survival time. Their results suggest that colon cancer-specific mortality increases as LINE-1 methylation decreases, independent of other molecular variables and clinical factors such as age, sex, year of diagnosis, and tumor location, stage, and grade.
A 30 percent decrease in LINE-1 methylation, for instance, roughly doubled the risk of colon cancer-specific mortality. And the lower the methylation level, the worse the patient outcomes.
The researchers speculated that the methylation changes associated with mortality may reflect genomic instability, transcriptional dysregulation, and the activation of oncogenes, inflammation, or oxidative stress.
Even so, the researchers noted, they had limited information about treatment differences between individuals. In addition, since the subjects in both the Nurses’ Health Study and the Health Professionals Follow-up Study were health professionals, they might not represent the general population.
Though the authors emphasized that follow-up studies are necessary, the team expressed enthusiasm about eventually applying the results clinically.
In another study, scheduled to appear online this week in the Proceedings of the National Academy of Sciences, researchers from Duke University, the National Cancer Institute, and Germany’s Georg-August University identified a 50-gene signature in early-stage colon cancer that predicts cancer recurrence. Along with its prognostic implications, preliminary results suggest that the signature, which was validated in two independent patient groups, may also provide clues for treating colon cancer.
“By examining gene expression in early-stage colon cancer tumors, we have found certain patterns that seem to put some patients at higher risk for recurrence,” lead author Katherine Garman, a gastroenterology researcher at Duke University, said in a statement. “By identifying these patients up front, we may be able to treat them in a targeted and proactive manner to prevent this recurrence and help them live longer and healthier lives.”
Garman and her team compiled gene expression data from publicly available datasets, assessing the expression patterns in 52 samples taken from individuals with known survival outcomes.
From these, the researchers found a 50-gene signature that appeared to predict individuals’ risk of cancer recurrence. This signature included RAS and TNF family genes previously implicated in carcinogenesis as well as genes in several pathways linked to metastasis. The team validated nine of the top ten differentially expressed genes using RT-PCR.
The team found that the signature could detect recurrence with more than 90 percent accuracy — regardless of the early colon cancer’s tumor, node, metastasis, or TNM stage.
Next, they tested the signature in two independent cohorts: 55 individuals followed for at least five years and 73 individuals followed for less than three years. The signature correctly classified nearly 70 percent of samples in the first cohort and in the second cohort the accuracy was just over 60 percent, though it correctly classified nearly all individuals in the low risk group.
The researchers attributed the slightly decreased accuracy to the inclusion of individuals with more advanced, stage III cancers in the validation cohort, coupled with shorter follow-up times.
The team also tested whether the gene signature was useful for guiding individuals’ treatment and identifying new drugs. Using the Broad Institute’s Connectivity Map, they assessed the gene expression profiles of cells treated with a range of drugs to look for profiles resembling the cancer recurrence signature.
Their research suggests that at least four drugs may influence the genes involved in the recurrence signature. Subsequent experiments indicated that cell lines with the high recurrence risk signature are sensitive to at least two of these compounds: the COX2 inhibitor celecoxib and the PI3K inhibitor LY-294002.
That, in turn, suggests it may be useful to test the treatments in those with the high-risk signature in order to identify patients who may benefit from such treatments rather than standard chemotherapy. The authors noted that such clinical trials are in the works.
“This is a perfect example of how science can change the way cancer care is practiced,” senior author Anil Potti, a researcher with Duke’s Institute for Genome Sciences and Policy, said in a statement. “We hope that advances such as this will individualize the treatment plans for patients with colon cancer and improve survival.”

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