title: Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma.
abstract: Genes involved in fetal lung development are thought to play crucial roles in the malignant transformation of adult lung cells. Consequently, the study of lung tumour biology in the context of lung development has the potential to reveal key developmentally relevant genes that play critical roles in lung cancer initiation/progression. Here, we describe for the first time a comprehensive characterization of miRNA expression in human fetal lung tissue, with subsequent identification of 37 miRNAs in non-small cell lung cancer (NSCLC) that recapitulate their fetal expression patterns. Nuclear factor I/B (NFIB), a transcription factor essential for lung development, was identified as a potential frequent target for these 'oncofetal' miRNAs. Concordantly, analysis of NFIB expression in multiple NSCLC independent cohorts revealed its recurrent underexpression (in ∼40-70% of tumours). Interrogation of NFIB copy number, methylation, and mutation status revealed that DNA level disruption of this gene is rare, and further supports the notion that oncofetal miRNAs are likely the primary mechanism responsible for NFIB underexpression in NSCLC. Reflecting its functional role in regulating lung differentiation, low expression of NFIB was significantly associated with biologically more aggressive subtypes and, ultimately, poorer survival in lung adenocarcinoma patients. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada. dbecker@bccrc.ca.
authors.forename: Daiana D
authors.initials: DD
authors.lastname: Becker-Santos
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.affiliation: Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: English
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Pikor
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Victor D
authors.initials: VD
authors.lastname: Martinez
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: May
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Vucic
authors.affiliation: Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: Margaret Ty
authors.initials: MT
authors.lastname: Luk
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Anita
authors.initials: A
authors.lastname: Carraro
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Jagoda
authors.initials: J
authors.lastname: Korbelik
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Piga
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Nicolas M
authors.initials: NM
authors.lastname: Lhomme
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Tsay
authors.affiliation: Department of Surgery, Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Yee
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Calum E
authors.initials: CE
authors.lastname: MacAulay
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D051839:NFI Transcription Factors / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate
chemical_list: D035683:MicroRNAs; D051839:NFI Transcription Factors; C110754:NFIB protein, human
keywords: lineage transcription factors; lung adenocarcinoma (LUAD); lung development; miRNA sequencing; miRNAs