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Hypermethylation of O6-Methylguanine-Dna Methyltransferase (Mgmt) Promoter As a Prognostic Biomarker for Stage Ii, III and Iv Colorectal Cancers
Annals of Oncology 25 (Supplement 4): iv58–iv84, 2014 doi:10.1093/annonc/mdu326.48
biomarkers 214P
abstracts
Y. Mori1, T. Nagasaka1, Y. Umeda1, R. Shiwaku2, R. Inada1, N. Nishida3, H. Kishimoto1, S. Kagawa1, H. Tanioka4, H. Mishima5, T. Fujiwara1, A. Goel6 1 Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JAPAN 2 Department of Oncology Pharmaceutical Care & Science., University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JAPAN 3 Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka, JAPAN 4 Department of Medical Oncology, Okayama Rosai Hospital, Okayama, JAPAN 5 Cancer Center, Aichi Medical University, Aichi, JAPAN 6 Division of Gastroenterology, Department of Internal Medicine and Charles A Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Centre, Dallas, TX, USA
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.
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/iv72/2240951 by guest on 25 October 2019
HYPERMETHYLATION OF O6-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT) PROMOTER AS A PROGNOSTIC BIOMARKER FOR STAGE II, III AND IV COLORECTAL CANCERS
biomarkers 214P
abstracts
Y. Mori1, T. Nagasaka1, Y. Umeda1, R. Shiwaku2, R. Inada1, N. Nishida3, H. Kishimoto1, S. Kagawa1, H. Tanioka4, H. Mishima5, T. Fujiwara1, A. Goel6 1 Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JAPAN 2 Department of Oncology Pharmaceutical Care & Science., University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, JAPAN 3 Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka, JAPAN 4 Department of Medical Oncology, Okayama Rosai Hospital, Okayama, JAPAN 5 Cancer Center, Aichi Medical University, Aichi, JAPAN 6 Division of Gastroenterology, Department of Internal Medicine and Charles A Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Centre, Dallas, TX, USA
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.
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/iv72/2240951 by guest on 25 October 2019
HYPERMETHYLATION OF O6-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT) PROMOTER AS A PROGNOSTIC BIOMARKER FOR STAGE II, III AND IV COLORECTAL CANCERS