Multiple pathways in the FGF signaling network are frequently deregulated by gene amplification in oral dysplasias
Open Access
- 2 June 2009
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 125 (9), 2219-2228
- https://doi.org/10.1002/ijc.24611
Abstract
Genetic alteration in oral premalignant lesions (OPLs), the precursors of oral squamous cell carcinomas (OSCCs), may represent key changes in disease initiation and development. We ask if DNA amplification occurs at this early stage of cancer development and which oncogenic pathways are disrupted in OPLs. Here, we evaluated 50 high‐grade dysplasias and low‐grade dysplasias that later progressed to cancer for gene dosage aberrations using tiling‐path DNA microarrays. Early occurrences of DNA amplification and homozygous deletion were frequently detected, with 40% (20/50) of these early lesions exhibiting such features. Expression for 88 genes in 7 recurrent amplicons were evaluated in 5 independent head and neck cancer datasets, with 40 candidates found to be overexpressed relative to normal tissues. These genes were significantly enriched in the canonical ERK/MAPK, FGF, p53, PTEN and PI3K/AKT signaling pathways (p = 8.95 × 10−3 to 3.18 × 10−2). These identified pathways share interactions in one signaling network, and amplification‐mediated deregulation of this network was found in 30.0% of these preinvasive lesions. No such alterations were found in 14 low‐grade dysplasias that did not progress, whereas 43.5% (10/23) of OSCCs were found to have altered genes within the pathways with DNA amplification. Multitarget FISH showed that amplification of EGFR and CCND1 can coexist in single cells of an oral dysplasia, suggesting the dependence on multiple oncogenes for OPL progression. Taken together, these findings identify a critical biological network that is frequently disrupted in high‐risk OPLs, with different specific genes disrupted in different individuals. © 2009 UICCFunding Information
- NIDCR (R01DE15965, R01DE13124)
- Genome Canada
- Canadian Institutes of Health Research
This publication has 73 references indexed in Scilit:
- Dysregulated molecular networks in head and neck carcinogenesisOral Oncology, 2009
- MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitorsInternational Journal of Cancer, 2009
- Epidermal growth factor receptor status and persistent activation of Akt and p44/42 MAPK pathways correlate with the effect of cetuximab in head and neck and colon cancer cell linesZeitschrift für Krebsforschung und Klinische Onkologie, 2008
- p16 Promoter Methylation Is a Potential Predictor of Malignant Transformation in Oral Epithelial DysplasiaCancer Epidemiology, Biomarkers & Prevention, 2008
- DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancersOncogene, 2008
- Fundamental Differences in Cell Cycle Deregulation in Human Papillomavirus–Positive and Human Papillomavirus–Negative Head/Neck and Cervical CancersCancer Research, 2007
- Recurrent FGFR1 amplification and high FGFR1 protein expression in oral squamous cell carcinoma (OSCC)Oral Oncology, 2007
- A Comprehensive Analysis of Common Copy-Number Variations in the Human GenomeAmerican Journal of Human Genetics, 2007
- Differential disruption of cell cycle pathways in small cell and non-small cell lung cancerBritish Journal of Cancer, 2006
- PTEN , a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate CancerScience, 1997