Abstract
BackgroundLymphotropism in oral squamous cell carcinoma (OSCC) is one of the most important prognostic factors of 5-year survival. In an effort to identify genes that may be responsible for the initiation of OSCC lymphotropism, we examined DNA copy number gains and losses and corresponding gene expression changes from tumor cells in metastatic lymph nodes of patients with OSCC.ResultsWe performed integrative analysis of DNA copy number alterations (CNA) and corresponding mRNA expression from OSCC cells isolated from metastatic lymph nodes of 20 patients using Affymetrix 250 K Nsp I SNP and U133 Plus 2.0 arrays, respectively. Overall, genome CNA accounted for expression changes in 31% of the transcripts studied. Genome region 11q13.2-11q13.3 shows the highest correlation between DNA CNA and expression. With a false discovery rate < 1%, 530 transcripts (461 genes) demonstrated a correlation between CNA and expression. Among these, we found two subsets that were significantly associated with OSCC (n = 122) when compared to controls, and with survival (n = 27), as tested using an independent dataset with genome-wide expression profiles for 148 primary OSCC and 45 normal oral mucosa. We fit Cox models to calculate a principal component analysis-derived risk-score for these two gene sets ('122-' or '27-transcript PC'). The models combining the 122- or 27-transcript PC with stage outperformed the model using stage alone in terms of the Area Under the Curve (AUC = 0.82 or 0.86 vs. 0.72, with p = 0.044 or 0.011, respectively).ConclusionsGenes exhibiting CNA-correlated expression may have biological impact on carcinogenesis and cancer progression in OSCC. Determination of copy number-associated transcripts associated with clinical outcomes in tumor cells with an aggressive phenotype (i.e., cells metastasized to the lymph nodes) can help prioritize candidate transcripts from high-throughput data for further studies.
Highlights
Lymphotropism in oral squamous cell carcinoma (OSCC) is one of the most important prognostic factors of 5-year survival
In an attempt to identify novel driver genes responsible for the OSCC metastasis, we utilized a recently developed protocol by our group for high-throughput profiling of DNA and RNA from the same cell population obtained by laser capture microdissection (LCM) to determine the association between DNA copy number aberration (CNA) and gene expression in tumor cells isolated from metastatic lymph nodes
DNA copy number aberrations in OSCC nodal metastasis CNA events were detected in all of the 20 OSCC lymph node metastases and in all chromosomal arms that were covered with SNP probes (13p, 14p, 15p, 21p and 22p were not covered by the Affymetrix 250 K Nsp SNP array)
Summary
Lymphotropism in oral squamous cell carcinoma (OSCC) is one of the most important prognostic factors of 5-year survival. In an attempt to identify novel driver genes responsible for the OSCC metastasis, we utilized a recently developed protocol by our group for high-throughput profiling of DNA and RNA from the same cell population obtained by laser capture microdissection (LCM) to determine the association between DNA copy number aberration (CNA) and gene expression in tumor cells isolated from metastatic lymph nodes. We reasoned that these cells would contain those changes in the genome and transcriptome that are essential to the lymphotropism of OSCC. We tested the hypothesis that since nodal metastases are associated with poor prognosis, the expression of copy number-associated genes from metastatic OSCC tumor cells is associated with survival
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