title: Recurring DNA copy number gain at chromosome 9p13 plays a role in the activation of multiple candidate oncogenes in progressing oral premalignant lesions.
abstract: Genomic alteration at chromosome 9p has been previously reported as a frequent and critical event in oral premalignancy. While this alteration is typically reported as a loss driven by selection for CDKN2A deactivation (at 9p21.3), we detect a recurrent DNA copy number gain of ~2.49 Mbp at chromosome 9p13 in oral premalignant lesions (OPLs) that later progressed to invasive lesions. This recurrent alteration event has been validated using fluorescence in situ hybridization in an independent set of OPLs. Analysis of publicly available gene expression datasets aided in identifying three oncogene candidates that may have driven selection for DNA copy number increases in this region (VCP, DCTN3, and STOML2). We performed in vitro silencing and activation experiments for each of these genes in oral cancer cell lines and found that each gene is independently capable of upregulating proliferation and anchorage-independent growth. We next analyzed the activity of each of these genes in biopsies of varying histological grades that were obtained from a diseased oral tissue field in a single patient, finding further molecular evidence of parallel activation of VCP, DCTN3, and STOML2 during progression from normal healthy tissue to invasive oral carcinoma. Our results support the conclusion that DNA gain at 9p13 is important to the earliest stages of oral tumorigenesis and that this alteration event likely contributes to the activation of multiple oncogene candidates capable of governing oral cancer phenotypes.
authors: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors: Rebecca
authors: R
authors: Towle
authors: Ivy F L
authors: IF
authors: Tsui
authors: Yuqi
authors: Y
authors: Zhu
authors: Sara
authors: S
authors: MacLellan
authors: Catherine F
authors: CF
authors: Poh
authors: Cathie
authors: C
authors: Garnis
mesh_terms: D001706:Biopsy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002899:Chromosomes, Human, Pair 9; D056915:DNA Copy Number Variations; D018450:Disease Progression; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D008969:Molecular Sequence Data; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology*; D009857:Oncogenes / Q000235:genetics*; D010641:Phenotype; D011230:Precancerous Conditions; D015533:Transcriptional Activation
keywords: 9p13; copy number gain; dysplasia; head and neck cancer; oncogene; oral squamous cell carcinoma; overexpression; premalignant lesion; progression