214P - Hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT) promoter as a prognostic biomarker for stage II, III and IV colorectal cancers

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Colon Cancer
Rectal Cancer
Translational Research
Presenter Yoshiko Mori
Citation Annals of Oncology (2014) 25 (suppl_4): iv58-iv84. 10.1093/annonc/mdu326
Authors Y. Mori1, T. Nagasaka2, Y. Umeda3, R. Shiwaku4, R. Inada4, N. Nishida5, H. Kishimoto3, S. Kagawa2, H. Tanioka6, H. Mishima7, T. Fujiwara3, A. Goel8
  • 1Department Of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 7008558 - Okayama/JP
  • 2Department Of Gastroenterological Surgery, Okayama University Hospital, 7008558 - Okayama/JP
  • 3Department Of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama/JP
  • 4Gastroenterological Surgery, Okayama University Graduate School of Medicine,Denistry and Pharmaseutical Sciences, 700-8558 - Okayama/JP
  • 5Department Of Gastroenterology And Hepatology, Kinki University Graduate School, 5898511 - Osaka/JP
  • 6Medical Oncology, Okayama Rosai Hospital, 712-8055 - Okayama/JP
  • 7Clinical Oncology, Aichi Medical University, 480-1195 - Nagakute/JP
  • 8Department Of Internal Medicine And Charles A, Baylor University Medical, Dallas/US

Abstract

Aim

The present study aimed to discover novel epigenetic biomarkers that could permit identification of CRC patients who are at high-risk of developing tumor recurrence following curative surgery and who are at high-risk of imminent tumor progression following treatments for unresectable cancer.

Methods

Given that previous studies have clearly shown that microsatellite stable (MSS) CRC with BRAF mutations have worse outcomes compared to other subgroups, in the initial discovery phase we analyzed a 17-gene methylation biomarker panel consisting of differentially methylated loci in BRAF mutant (V600E) CRCs with microsatellite instability (MSI) and MSS. In the validation phase, we analyzed an independent cohort of 255 stage II/III CRCs that underwent curative resection and 103 stage IV CRCs.

Results

We identified that among the 17-genes methylation panel; only MGMT methylation levels were predictive of disease recurrence in CRC. Extensive methylation of the MGMT promoter region was observed in 22% of stage II/III and 16% of stage IV CRCs, and this was significantly associated with relapse -free survival (RFS) (p = 0.03 by Wilcoxon test), but not with overall survival (p = 0.96 by Wilcoxon test) in stage II/III CRC following curative resection. By using Cox proportional hazards regression, for all stage II and III cases, the relative risk ratio for RFS was 2.2 (95%CI; 1.1 to 5.6, p = 0.0359) in MGMT unmethylated vs. methylated CRCs and was 0.62 (0.034 to 3.2, p = 0.627) in MSI vs. MSS CRCs. Of 103 stage IV CRCs, 69(68%) patients were diagnosed as unresectable (unresectable group) cases and 32 (32%) were resectable (resectable group). MGMT methylation was significantly improved overall survival in unresectable group (HR = 0.43 (0.17 to 0.94), p = 0.03, Cox proportional hazards regression).

Conclusions

Our data firstly highlight the importance of MGMT methylation status as one of the promising predictive biomarkers that can robustly identify patients who are at risk for disease recurrence in patients following curative surgery in stage III CRC patients and predict the outcomes of stage IV CRC patients with unresectable disease lesions at the time of diagnosis.

Disclosure

All authors have declared no conflicts of interest.