caa a22 4500 44531611X CHVBK 20180317142647.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s10552-010-9698-z doi (NATIONALLICENCE)springer-10.1007/s10552-010-9698-z MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers [Elektronische Daten] [Kaori Shima, Teppei Morikawa, Yoshifumi Baba, Katsuhiko Nosho, Maiko Suzuki, Mai Yamauchi, Marika Hayashi, Edward Giovannucci, Charles Fuchs, Shuji Ogino] Objective: O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme. MGMT promoter hypermethylation and epigenetic silencing often occur as early events in carcinogenesis. However, prognostic significance of MGMT alterations in colorectal cancer remains uncertain. Methods: Utilizing a database of 855 colon and rectal cancers in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected MGMT promoter hypermethylation in 325 tumors (38%) by MethyLight and loss of MGMT expression in 37% (247/672) of tumors by immunohistochemistry. We assessed the CpG island methylator phenotype (CIMP) using eight methylation markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and LINE-1 (L1) hypomethylation, TP53 (p53), and microsatellite instability (MSI). Results: MGMT hypermethylation was not associated with colorectal cancer-specific mortality in univariate or multivariate Cox regression analysis [adjusted hazard ratio (HR)=1.03; 95% confidence interval (CI), 0.79-1.36] that adjusted for clinical and tumor features, including CIMP, MSI, and BRAF mutation. Similarly, MGMT loss was not associated with patient survival. MGMT loss was associated with G>A mutations in KRAS (p=0.019) and PIK3CA (p=0.0031). Conclusions: Despite a well-established role of MGMT aberrations in carcinogenesis, neither MGMT promoter methylation nor MGMT loss serves as a prognostic biomarker in colorectal cancer. Springer Science+Business Media B.V., 2010 Colon cancer nationallicence MGMT nationallicence Hypermethylation nationallicence Epigenetics nationallicence Clinical outcome nationallicence BMI : Body mass index nationallicence CI : Confidence interval nationallicence CIMP : CpG island methylator phenotype nationallicence HR : Hazard ratio nationallicence MGMT : O6-methylguanine-DNA methyltransferase nationallicence MSI : Microsatellite instability nationallicence MSS : Microsatellite stable nationallicence OR : Odds ratio nationallicence Shima Kaori Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut Morikawa Teppei Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut Baba Yoshifumi Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut Nosho Katsuhiko Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut Suzuki Maiko Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut Yamauchi Mai Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut Hayashi Marika Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut Giovannucci Edward Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA aut Fuchs Charles Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut Ogino Shuji Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut Cancer Causes & Control Springer Netherlands 22/2(2011-02-01), 301-309 0957-5243 22:2<301 2011 22 10552 https://doi.org/10.1007/s10552-010-9698-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10552-010-9698-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Shima Kaori Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Morikawa Teppei Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Baba Yoshifumi Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Nosho Katsuhiko Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Suzuki Maiko Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Yamauchi Mai Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Hayashi Marika Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Giovannucci Edward Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Fuchs Charles Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 700 1- Ogino Shuji Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA aut NATIONALLICENCE 773 0- Cancer Causes & Control Springer Netherlands 22/2(2011-02-01), 301-309 0957-5243 22:2<301 2011 22 10552 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer