title: Prognostic and predictive significance of long interspersed nucleotide element-1 methylation in advanced-stage colorectal cancer.
abstract: Hypomethylation of Long Interspersed Nucleotide Element-1 (LINE-1) is associated with worse prognosis in colorectal cancer (CRC). However, little is known about the relevance of this marker for the prognosis and response to chemotherapy of metastatic and recurrent (advanced-stage) CRC. Our aim was therefore to investigate whether tumor LINE-1 hypomethylation correlates with patient survival and with response to 5-fluorouracil (5-FU)/ oxaliplatin (FOLFOX) chemotherapy in advanced-stage CRC.
  
  
  
  The study included 40 CRC patients who developed metastasis or local recurrence after surgery and subsequently underwent FOLFOX therapy. Progression-free and overall survival were estimated using the Kaplan-Meier method. LINE-1 methylation levels in formalin-fixed and paraffin-embedded primary tumor tissues were measured by MethyLight assay and correlated with patient survival. In vitro analyses were also conducted with human colon cancer cell lines having different LINE-1 methylation levels to examine the effects of 5-FU and oxaliplatin on LINE-1 activity and DNA double-strand-breaks.
  
  
  
  Patients with LINE-1 hypomethylation showed significantly worse progression-free (median: 6.6 vs 9.4 months; P = 0.02) and overall (median: 16.6 vs 23.2 months; P = 0.01) survival following chemotherapy compared to patients with high methylation. LINE-1 hypomethylation was an independent factor for poor prognosis (P = 0.018) and was associated with a trend for non-response to FOLFOX chemotherapy. In vitro analysis showed that oxaliplatin increased the LINE-1 score in LINE-1-expressing (hypomethylated) cancer cells, thereby enhancing and prolonging the effect of 5-FU against these cells. This finding supports the observed correlation between tumor LINE-1 methylation and response to chemotherapy in CRC patients.
  
  
  
  Tumor LINE-1 hypomethylation is an independent marker of poor prognosis in advanced-stage CRC and may also predict non-response to combination FOLFOX chemotherapy. Prospective studies are needed to optimize the measurement of tumor LINE-1 methylation and to confirm its clinical impact, particularly as a predictive marker.
authors.affiliation: Department of General and Cardiothoracic Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan. kanekomami@ipch.jp.|Department of Gastrointestinal Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Japan. kanekomami@ipch.jp.|Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. kanekomami@ipch.jp.
authors.forename: Mami
authors.initials: M
authors.lastname: Kaneko
authors.affiliation: Department of General and Cardiothoracic Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kotake
authors.affiliation: Department of Gastrointestinal Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Bando
authors.affiliation: Department of Gastrointestinal Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of General and Cardiothoracic Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Takemura
authors.affiliation: Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Minamoto
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D045325:HCT116 Cells; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D011379:Prognosis; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil
keywords: Colorectal cancer; LINE-1 elements; Metastasis; Oxaliplatin; Prognosis