title: Disruption of NCOA2 by recurrent fusion with LACTB2 in colorectal cancer.
abstract: Whole-genome and transcriptome sequencing were used to discover novel gene fusions in a case of colon cancer. A tumor-specific LACTB2-NCOA2 fusion originating from intra-chromosomal rearrangement of chromosome 8 was identified at both DNA and RNA levels. Unlike conventional oncogenic chimeric proteins, the fusion product lacks functional domain from respective genes, indicative of an amorphic rearrangement. This chimeric LACTB2-NCOA2 transcript was detected in 6 out of 99 (6.1%) colorectal cancer (CRC) cases, where NCOA2 was significantly downregulated. Enforced expression of wild-type NCOA2 but not the LACTB2-NCOA2 fusion protein impaired the pro-tumorigenic phenotypes of CRC cells, whereas knockdown of endogenous NCOA2 in normal colonocytes had opposite effects. Mechanistically, NCOA2 inhibited Wnt/β-catenin signaling through simultaneously upregulating inhibitors and downregulating stimulators of Wnt/β-catenin pathway. Collectively, our data supports that NCOA2 is a novel negative growth regulatory gene repressing the Wnt/β-catenin pathway in CRC, where recurrent fusion with LACTB2 contributes to its disruption.
authors.affiliation: Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.|Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: W K K
authors.initials: WK
authors.lastname: Wu
authors.affiliation: Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.|Department of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: N
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: M T V
authors.initials: MT
authors.lastname: Chan
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: S S M
authors.initials: SS
authors.lastname: Ng
authors.affiliation: Institute of Digestive Disease, Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: J J Y
authors.initials: JJ
authors.lastname: Sung
mesh_terms: D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D015321:Gene Rearrangement; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism
chemical_list: C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D015514:Oncogene Proteins, Fusion; D051176:beta Catenin; C000607856:LACTB2 protein, human; D001618:beta-Lactamases
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