Epigenetic Homogeneity Within Colorectal Tumors Predicts Shorter Relapse-Free and Overall Survival Times for Patients With Locoregional Cancer

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• 作者：Anna Martí ; nez-Cardú ; s¹ ; ^&lowast ; ; Sebastian Moran¹ ; ^&lowast ; ; Eva Musulen² ; Cá ; tia Moutinho¹ ; Jose L. Manzano³ ; Eva Martinez-Balibrea⁴ ; Montserrat Tierno⁴ ; Elena É ; lez⁵ ; Stefania Landolfi⁶ ; Patricia Lorden¹ ; Carles Arribas¹ ; Fabian M&uuml ; ller⁷ ; Christoph Bock⁷ ; ⁸ ; Josep Tabernero⁵ ; Manel Esteller¹ ; ⁹ ; ¹⁰ ; ^{mesteller@idibell.cat" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Colorectal Cancer ; Epigenetics ; DNA Methylation ; Heterogeneity
• 刊名：Gastroenterology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：151
• 期：5
• 页码：961-972
• 全文大小：4218 K

文摘

There are few validated biomarkers that can be used to predict outcomes for patients with colorectal cancer. Part of the challenge is the genetic and molecular heterogeneity of colorectal tumors not only among patients, but also within tumors. We have explored intratumor heterogeneity at the epigenetic level, due to its dynamic nature. We analyzed DNA methylation profiles of the digestive tract surface and the central bulk and invasive front regions of colorectal tumors.

Methods

We determined the DNA methylation profiles of >450,000 CpG sites in 3 macrodissected regions of 79 colorectal tumors and 23 associated liver metastases, obtained from 2 hospitals in Spain. We also analyzed samples for KRAS and BRAF mutations, 499,170 single nucleotide polymorphisms, and performed immunohistochemical analyses.

Results

We observed differences in DNA methylation among the 3 tumor sections; regions of tumor−host interface differed the most from the other tumor sections. Interestingly, tumor samples collected from areas closer to the gastrointestinal transit most frequently shared methylation events with metastases. When we calculated individual coefficients to quantify heterogeneity, we found that epigenetic homogeneity was significantly associated with short time of relapse-free survival (log-rank P = .037) and short time of overall survival (log-rank P = .026) in patients with locoregional colorectal cancer.

Conclusions

In an analysis of 79 colorectal tumors, we found significant heterogeneity in patterns of DNA methylation within each tumor; the level of heterogeneity correlates with times of relapse-free and overall survival.