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Poster display session

2741 - Impact of global epigenetics machinery on clinical outcome of colorectal cancer patients treated with fluoropyrimidine-based therapy

Date

11 Sep 2017

Session

Poster display session

Topics

Translational Research;  Colon and Rectal Cancer

Presenters

Mariam Fouad

Citation

Annals of Oncology (2017) 28 (suppl_5): v595-v604. 10.1093/annonc/mdx391

Authors

M.A. Fouad1, S.E. Salem2, M. Hussein2, A. Zekri1, D. Mohammed1, H. Hafez1, S. Shouman1

Author affiliations

  • 1 Cancer Biology, National cancer Institute-Cairo University, 11796 - Cairo/EG
  • 2 Medical Oncology, National cancer Institute-Cairo University, 11796 - Cairo/EG
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Resources

Abstract 2741

Background

The pathogenesis of colorectal cancer (CRC) is complex and influenced by many factors related to genetic, epigenetics and chronic inflammatory processes.

Methods

This is a prospective study, conducted on 102 Egyptian patients, diagnosed with CRC. Blood samples were collected at baseline and after 3 & 6 months of receiving fluoropyrimidine (FP) based therapy. DNA methylation was measured by LC/MS/MS spectroscopy, acetylated histones (H3) and (H4) were measured by ELISA and RNA expression of FP metabolizing enzymes (TS, TP and DPD), DNA methyl transferases (DNMT3A and B) in addition to inflammatory markers (COX2, IL6, and IL1B) by qRT-PCR.

Results

The median age of the studied patients was 46 years, 47% of them were ≤ 45 years. Forty patients (38.8%) had rectal cancer, they exhibited significant H3 hyperacetylation and upregulation of COX2 and IL1B along with significantly lower median overall survival compared to colonic patients (14.6 versus 23 months respectively). FP therapy produced significant decrease in global methylation, acetylated H3 & H4 levels, downregulation in TP and DNMT3B but significant upregulation in TS and DPD over treatment time. Significant positive correlations were found between global methylation and IL1B (r2= 0.25, P = 0.01), acetylated H3 with DPD and COX2 (r2= 0.28, P = 0.02 and r2= 0.27, P = 0.03 respectively) and 5 methylated cytosine content (5MC) with DNMT3A and IL6 (r2= 0.25, P = 0.04 and r2= 0.34, P = 0.004 respectively). Overexpression of COX2 > 17 had a significant poor prognostic effect on overall and event free survivals (HR = 0.58, P = 0.003 and HR = 0.72, P = 0.008 respectively). Also patients who had global methylation> 30 showed significant reduced event free survival by 39% (P = 0.04).

Conclusions

Global methylation and H3 acetylation regulated COX2, IL6 and IL1B which were not affected by the therapy, however H3 upregulated TS and DPD. Rectal cancer patients showed significant H3 hyperacetylation, upregulation of COX2 and IL1B along with significant lower overall survival.

Clinical trial identification

Legal entity responsible for the study

National Cancer Institute, Cairo University

Funding

National Cancer Institute, Cairo University

Disclosure

All authors have declared no conflicts of interest.

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