title: Novel mRNA isoforms and mutations of uridine monophosphate synthetase and 5-fluorouracil resistance in colorectal cancer.
abstract: The drug fluorouracil (5-FU) is a widely used antimetabolite chemotherapy in the treatment of colorectal cancer. The gene uridine monophosphate synthetase (UMPS) is thought to be primarily responsible for conversion of 5-FU to active anticancer metabolites in tumor cells. Mutation or aberrant expression of UMPS may contribute to 5-FU resistance during treatment. We undertook a characterization of UMPS mRNA isoform expression and sequence variation in 5-FU-resistant cell lines and drug-naive or -exposed primary and metastatic tumors. We observed reciprocal differential expression of two UMPS isoforms in a colorectal cancer cell line with acquired 5-FU resistance relative to the 5-FU-sensitive cell line from which it was derived. A novel isoform arising as a consequence of exon skipping was increased in abundance in resistant cells. The underlying mechanism responsible for this shift in isoform expression was determined to be a heterozygous splice site mutation acquired in the resistant cell line. We developed sequencing and expression assays to specifically detect alternative UMPS isoforms and used these to determine that UMPS was recurrently disrupted by mutations and aberrant splicing in additional 5-FU-resistant colorectal cancer cell lines and colorectal tumors. The observed mutations, aberrant splicing and downregulation of UMPS represent novel mechanisms for acquired 5-FU resistance in colorectal cancer.
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Griffith
authors.forename: J C
authors.initials: JC
authors.lastname: Mwenifumbo
authors.forename: P Y
authors.initials: PY
authors.lastname: Cheung
authors.forename: J E
authors.initials: JE
authors.lastname: Paul
authors.forename: T J
authors.initials: TJ
authors.lastname: Pugh
authors.forename: M J
authors.initials: MJ
authors.lastname: Tang
authors.forename: S
authors.initials: S
authors.lastname: Chittaranjan
authors.forename: R D
authors.initials: RD
authors.lastname: Morin
authors.forename: J K
authors.initials: JK
authors.lastname: Asano
authors.forename: A A
authors.initials: AA
authors.lastname: Ally
authors.forename: L
authors.initials: L
authors.lastname: Miao
authors.forename: A
authors.initials: A
authors.lastname: Lee
authors.forename: S Y
authors.initials: SY
authors.lastname: Chan
authors.forename: G
authors.initials: G
authors.lastname: Taylor
authors.forename: T
authors.initials: T
authors.lastname: Severson
authors.forename: Y-C
authors.initials: YC
authors.lastname: Hou
authors.forename: O L
authors.initials: OL
authors.lastname: Griffith
authors.forename: G S W
authors.initials: GS
authors.lastname: Cheng
authors.forename: K
authors.initials: K
authors.lastname: Novik
authors.forename: R
authors.initials: R
authors.lastname: Moore
authors.forename: M
authors.initials: M
authors.lastname: Luk
authors.forename: D
authors.initials: D
authors.lastname: Owen
authors.forename: C J
authors.initials: CJ
authors.lastname: Brown
authors.forename: G B
authors.initials: GB
authors.lastname: Morin
authors.forename: S
authors.initials: S
authors.lastname: Gill
authors.forename: I T
authors.initials: IT
authors.lastname: Tai
authors.forename: M A
authors.initials: MA
authors.lastname: Marra
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009962:Orotate Phosphoribosyltransferase / Q000235:genetics* / Q000378:metabolism; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000235:genetics* / Q000378:metabolism; D059368:RNA Isoforms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D009097:Multienzyme Complexes; D059368:RNA Isoforms; D012333:RNA, Messenger; C027157:uridine 5'-monophosphate synthase; D009962:Orotate Phosphoribosyltransferase; D009964:Orotidine-5'-Phosphate Decarboxylase; D005472:Fluorouracil