title: DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer.
abstract: Anti-epidermal growth factor receptor (EGFR) treatment is an effective option for metastatic colorectal cancer (CRC) treatment. However, there are few reliable biomarkers to predict the clinical response to anti-EGFR treatment. We investigated the genome-wide DNA methylation status in metastatic colorectal cancer to identify associations between the methylation status and clinical response to anti-EGFR antibody. We retrospectively reviewed the medical records of 97 patients (45 patients for the first cohort and 52 patients for the second cohort) who received anti-EGFR treatment for KRAS wild-type metastatic CRC. Then we analyzed the associations between genome-wide DNA methylation status and clinical response to anti-EGFR treatment, and evaluated the predictive power and value of the methylation status statistically. As a result, each cohort was classified into highly methylated CRC and low methylated CRC subgroups by unsupervised clustering analyses. In the first cohort, clinical outcomes were significantly better in the low methylated CRC subgroup than in the highly methylated CRC subgroup (response rate, 35.7% vs 6.3%, P = 0.03; disease control rate, 75% vs 31.3%, P = 0.005; hazard ratio for progression-free survival, 0.27; 95% confidence interval, 0.13-0.57, P < 0.001; overall survival, 0.19; 95% confidence interval, 0.06-0.54, P < 0.001). These results were reproducible in the second cohort. The genome-wide methylation status was a predictive factor of progression-free survival and overall survival independently of RAS mutation status. In conclusion, we found that the genome-wide DNA methylation status is a powerful epigenetic predictor of anti-EGFR treatment in patients with KRAS wild-type metastatic colorectal cancer (UMIN000005490).
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.|Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Ouchi
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.|Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tatsuno
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.|Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.|Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.|Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Shimodaira
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.|Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Ishioka
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Anti-EGFR treatment; DNA methylation; biomarker; colorectal cancer; molecular targeted therapy