Epigenetic Similarity in Cancer Cells Characterizes More Aggressive Tumors

Few biomarkers for predicting outcomes of patients with colorectal cancer have been validated. This is in part due to the genetic and molecular heterogeneity of colorectal tumors not only among different patients, but also within the tumors themselves.

To better understand the puzzle of tumor cell heterogeneity, investigators at IDIBELL-Bellvitge Biomedical Research Institute (Barcelona, Spain) analyzed DNA methylation profiles of the digestive tract surface and the central bulk and invasive front regions of 79 colorectal tumors and 23 associated liver metastases, obtained from two hospitals in Spain. They also analyzed samples for KRAS and BRAF mutations, 499,170 single nucleotide polymorphisms, and performed immunohistochemical analyses.

Results showed that among three defined tumor sections, differences in DNA methylation were most pronounced at the site of the tumor-host interface. Tumor samples collected from areas closer to the gastrointestinal transit most frequently shared methylation events with metastases. When individual coefficients were calculated to quantify heterogeneity, epigenetic homogeneity was found to be significantly associated with short time of relapse-free survival and short time of overall survival.

"In patients with colorectal cancer, we determined the epigenome of three regions of each individual tumor. The area looking at the beginning of the digestive tract, central and growing into the blood vessels results demonstrate the existence of intratumoral heterogeneity, which means that each region has differences," said senior author Dr. Manel Esteller, director of the epigenetics and cancer biology program at Bellvitge Biomedical Research Institute. "The more epigenetically different region is the invasive front, the area that interacts with adjacent normal tissues. We have also seen that the intratumoral region most similar to metastatic stages is the oldest of the tumor, which suggests spreading even in apparently early stages. Furthermore, data show that the more similar the three regions are, the more aggressive the tumor is, just as if the cell population with more proliferation capacity had already been selected. Measurements of the level of molecular heterogeneity of tumors could then be used as predictors of their prognosis and potential to acquire resistance to therapies."

The study was published in the August 10, 2016, online edition of the journal Gastroenterology.

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IDIBELL-Bellvitge Biomedical Research Institute