title: NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer.
abstract: Esophageal squamous cancer (ESC) is one of the most aggressive tumors of the gastrointestinal tract. A combination of chemotherapy and radiation therapy (CRT) has improved the clinical outcome, but the molecular background determining the effectiveness of therapy remains unknown. NRF2 is a master transcriptional regulator of stress adaptation, and gain of-function mutation of NRF2 in cancer confers resistance to stressors including anticancer therapy. Direct resequencing analysis revealed that Nrf2 gain-of-function mutation occurred recurrently (18/82, 22%) in advanced ESC tumors and ESC cell lines (3/10). The presence of Nrf2 mutation was associated with tumor recurrence and poor prognosis. Short hairpin RNA-mediated down-regulation of NRF2 in ESC cells that harbor only mutated Nrf2 allele revealed that themutant NRF2 conferred increased cell proliferation, attachment-independent survival, and resistance to 5-fluorouracil and γ-irradiation. Based on the Nrf2 mutation status, gene expression signatures associated with NRF2 mutation were extracted from ESC cell lines, and their potential utility for monitoring and prognosis was examined in a cohort of 33 pre-CRT cases of ESC. The molecular signatures of NRF2 mutation were significantly predictive and prognostic for CRT response. In conclusion, recurrent NRF2 mutation confers malignant potential and resistance to therapy in advanced ESC, resulting in a poorer outcome. Molecular signatures of NRF2 mutation can be applied as predictive markers of response to CRT, and efficient inhibition of aberrant NRF2 activation could be a promising approach in combination with CRT.
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. tashibat@ncc.go.jp
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Akiko
authors.initials: A
authors.lastname: Kokubu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Saito
authors.forename: Mako
authors.initials: M
authors.lastname: Narisawa-Saito
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Aoyagi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yoshimatsu
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tachimori
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kushima
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001483:Base Sequence; D014408:Biomarkers, Tumor; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D059248:Chemoradiotherapy; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D005720:Gamma Rays; D006801:Humans; D008297:Male; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering; D011836:Radiation Tolerance / Q000235:genetics; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D005472:Fluorouracil