title: Next-generation sequencing of colorectal cancers in chinese: identification of a recurrent frame-shift and gain-of-function Indel mutation in the TFDP1 gene.
abstract: Abstract Re-sequencing of target genes is a highly effective approach for identifying mutations in cancers. Mutations, including indels (insertions, deletions, and the combination of the two), play important roles in carcinogenesis. Combining genomic DNA capture using high-density oligonucleotide microarrays (NimbleGen, Inc.) with next-generation high-throughput sequencing, we identified approximately 1600 indels for colorectal cancers in the Chinese population. Among them, 5 indels were localized to exonic regions of genes, including the TFDP1 (transcription factor Dp-1) gene. TFDP1 is an important transcription factor that coordinates with E2F proteins, thereby promoting transcription of E2F target genes and regulating the cell cycle and differentiation. We report here the identification of a recurrent frame-shift indel mutation (named indel84) in the TFDP1 gene in colorectal cancers by next-generation sequencing. We found in a validation set that TFDP1 indel84 is present in 70% of colorectal cancer (CRC) tissues. Wild-type TFDP1 encodes a protein of 410 amino acids with a potential DNA binding site at its N-terminal followed by several functional protein domains. The TFDP1 indel cDNA would generate an alternative TFDP1 protein missing the first 120 amino acids and potentially affecting the DNA binding domain. We further demonstrated that the TFDP1 indel84 mutation generated a gain-of-function phenotype by increasing cell proliferation, migration, and invasion of CRC cells. Our study identified a key molecular event for CRC that might have great diagnostic and therapeutic potentials.
authors.affiliation: 1 Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, College of Medicine, Zhejiang University , Hangzhou, Zhejiang Province, China .
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Fan
authors.initials: F
authors.lastname: Zhou
authors.forename: Jianbo
authors.initials: J
authors.lastname: Sun
authors.forename: Lisha
authors.initials: L
authors.lastname: Li
authors.forename: Chengmeng
authors.initials: C
authors.lastname: Jin
authors.forename: Jiaofang
authors.initials: J
authors.lastname: Shao
authors.forename: Huawei
authors.initials: H
authors.lastname: Jiang
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.forename: Shu
authors.initials: S
authors.lastname: Zheng
authors.forename: Biaoyang
authors.initials: B
authors.lastname: Lin
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement; D002681:China; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D050680:Transcription Factor DP1 / Q000235:genetics*
chemical_list: C493735:TFDP1 protein, human; D050680:Transcription Factor DP1