[show abstract][hide abstract] ABSTRACT: Squamous cell carcinomas (SqCCs) arise in a wide range of tissues including skin, lung, and oral mucosa. Although all SqCCs are epithelial in origin and share common nomenclature, these cancers differ greatly with respect to incidence, prognosis, and treatment. Current knowledge of genetic similarities and differences between SqCCs is insufficient to describe the biology of these cancers, which arise from diverse tissue origins. In this paper we provide a general overview of whole genome approaches for gene and pathway discovery and highlight the advancement of integrative genomics as a state-of-the-art technology in the study of SqCC genetics.
[show abstract][hide abstract] ABSTRACT: Cell lines are invaluable model systems for the investigation of cancer. Knowledge of the molecular alterations that exist within cell models is required to define the mechanisms governing cellular phenotypes.
Five tongue squamous cell carcinomas cell lines and 1 submaxillary salivary gland epidermoid carcinoma cell line were analyzed for copy number and mRNA expression by tiling-path DNA microarrays and Agilent Whole Human Genome Oligoarrays, respectively.
Integrative analysis of genetic and expression alterations revealed the molecular landscape of each cell line. Molecular results for individual cell lines and across all samples have been summarized and made available for easy reference.
Our integrative genomic analyses have defined the DNA and RNA alterations for each individual line. These data will be useful to anyone modeling oral cancer behavior, providing a molecular context that will be useful for deciphering cell phenotypes.
Head & Neck 12/2009; 32(9):1143-60. · 2.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: Oral cancer is a complex disease that is characterized by histologic and genetic heterogeneity. The evolution and progression of this disease is thought to result from the accumulation of alterations in molecular pathways. Although the oral cavity is accessible for routine screening of suspicious lesions, gene alterations are known to accrue in histologically normal tissues. Therefore, some cancer forerunners may remain undetected clinically or histologically. Recently emerging optical and molecular technologies have provided a powerful means for redefining the extent of the field of alteration. Often this means expanding upon regions detectable with standard white light approaches. In this report, we used a newly developed optical technique, direct fluorescence visualization, to define a contiguous field that extended beyond the margins of a clinically visible oral squamous cell carcinoma. Multiple biopsies were taken within this contiguous optically altered field. Genome alterations detected for each specimen were compared to define whether each lesion arose independently or as a consequence of a shared progenitor cell. Our results indicate that the field effect of oral cancer is extremely dynamic, with different genetic alterations present in different biopsies within a field. This case study also demonstrated that 2 genetically unrelated squamous cell carcinoma could be developed within 10 mm at the right lateral tongue of this patient. These findings provide evidence for the importance to implement optical technologies in defining surgical margins and support the use of whole genome technologies in the diagnosis of clonal versus independent lesions of the oral cavity, which may have implications on treatment strategies.
The American journal of surgical pathology 11/2009; 33(11):1732-8. · 4.06 Impact Factor
[show abstract][hide abstract] 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 x 10(-3) to 3.18 x 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.
International Journal of Cancer 07/2009; 125(9):2219-28. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: The study of oral premalignant lesions (OPL) is crucial to the identification of initiating genetic events in oral cancer. However, these lesions are minute in size, making it a challenge to recover sufficient DNA from microdissected cells for comprehensive genomic analysis. As a step toward identifying genetic aberrations associated with oral cancer progression, we used tiling-path array comparative genomic hybridization to compare alterations on chromosome 3p for 71 OPLs against 23 oral squamous cell carcinomas. 3p was chosen because although it is frequently altered in oral cancers and has been associated with progression risk, its alteration status has only been evaluated at a small number of loci in OPLs. We identified six recurrent losses in this region that were shared between high-grade dysplasias and oral squamous cell carcinomas, including a 2.89-Mbp deletion spanning the FHIT gene (previously implicated in oral cancer progression). When the alteration status for these six regions was examined in 24 low-grade dysplasias with known progression outcome, we observed that they occurred at a significantly higher frequency in low-grade dysplasias that later progressed to later-stage disease (P < 0.003). Moreover, parallel analysis of all profiled tissues showed that the extent of overall genomic alteration at 3p increased with histologic stage. This first high-resolution analysis of chromosome arm 3p in OPLs represents a significant step toward predicting progression risk in early preinvasive disease and provides a keen example of how genomic instability escalates with progression to invasive cancer.
Cancer Prevention Research 11/2008; 1(6):424-9. · 4.89 Impact Factor
[show abstract][hide abstract] ABSTRACT: The study of pathway disruption is key to understanding cancer biology. Advances in high throughput technologies have led to the rapid accumulation of genomic data. The explosion in available data has generated opportunities for investigation of concerted changes that disrupt biological functions, this in turns created a need for computational tools for pathway analysis. In this review, we discuss approaches to the analysis of genomic data and describe the publicly available resources for studying biological pathways.