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Diverse repetitive element RNA expression defines epigenetic and immunologic features of colon cancer

Niyati Desai1,2, Dipti Sajed2, Kshitij S Arora1,2,3

  • 1Massachusetts General Hospital Cancer Center.

JCI Insight
|February 15, 2017
PubMed

Insights

Predicting responses to epigenetic therapies like 5-azacitidine (AZA) in colon cancer is challenging. Distinct repeat RNA patterns, specifically LINE-1 and HERV-H, can classify tumors and predict drug response.

Area of Science:

  • Genomics
  • Cancer Biology
  • Epigenetics

Background:

  • Epigenetic therapies show promise for cancer treatment, but predicting patient response remains difficult.
  • Differentiating direct cytotoxic and immunomodulatory effects of epigenetic drugs is a key challenge.
  • 5-azacitidine (AZA), a DNA-hypomethylating agent, exhibits distinct effects in colon cancer, potentially linked to repeat RNA derepression.

Purpose of the Study:

  • To investigate the role of repeat RNAs, specifically LINE-1 and HERV-H, in colon cancer.
  • To determine if distinct repeat RNA expression patterns can serve as biomarkers for epigenetic drug response.
  • To explore the correlation between repeat RNA expression and tumor biological states and immune infiltrates.

Main Methods:

  • RNA sequencing and RNA in situ hybridization were used to detect LINE-1 and HERV-H expression in colon cancers.
  • Analysis of expression patterns in relation to global DNA methylation, TP53 status, and FOXP3+ Treg infiltrates.
  • Correlation of repeat RNA expression with responsiveness to 5-azacitidine (AZA).

Main Results:

  • LINE-1 and HERV-H subtypes exhibit distinct expression patterns in colon cancer.
  • Low LINE-1 expression correlates with global DNA hypermethylation, wild-type TP53, and AZA responsiveness.
  • HERV-H expression is linked to differences in FOXP3+ Treg tumor infiltrates and is not concordant with LINE-1 expression.

Conclusions:

  • Distinct repeat RNA expression patterns define novel molecular classifications of colon cancer.
  • These patterns can serve as biomarkers to differentiate cytotoxic from immunomodulatory effects of epigenetic drugs.
  • Understanding repeat RNA heterogeneity provides insights into predicting and monitoring epigenetic therapy response.

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