Integrative analysis of DNA copy number and gene expression in metastatic oral squamous cell carcinoma identifies genes associated with poor survival

Xu Chang, Yan Liu, Wang Pei, Fan Wenhong, Rue, Upton, Houck, Lohavanichbutr Pawadee, Doody, Futran, Zhao Lue, Schwartz, Chen Chu, Méndez Eduardo

Description

Lymphotropism 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. Results We 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). Conclusions Genes 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.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2010
• Nombre de lectures: 18
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Xu et al.  Molecular Cancer 2010, 9 :143 http://www.molecular-canc er.com/content/9/1/143

R E S E A R C H  Open Access I Re n se t a e rch grative analysis of DNA copy number and gene expression in metastatic oral squamous cell carcinoma identifies genes associated with poor survival Chang Xu 1 , Yan Liu 2 , Pei Wang 3 , Wenhong Fan 2 , Tessa C Rue 4 , Melissa P Upton 5 , John R Houck 6 , Pawadee Lohavanichbutr 6 , David R Doody 6 , Neal D Futran 1 , Lue Ping Zhao 2,4 , Stephen M Schwartz 6,7 , Chu Chen 1,6,7   and Eduardo Méndez* 1,6,8,9

Background which OSCC cells spread from the primary site to local Oral squamous cell carcinoma (OSCC) is the sixth most lymph nodes is not well understood. Transcriptome pro- common cancer worldwide. The presence of lymph node filing has been used to gain insights into this process [1,5- metastasis is associated with a 50% decrease in 5-yr sur- 7], but the function of many of the proposed differentially vival, and is the single most important prognostic factor expressed transcripts is unknown. To improve the likeli- identified to date [1-4]. However, the mechanisms by hood of finding genes driving the carcinogenic process, several groups have exploited the common feature of * Correspondence: [e-mail] genomic instability in cancer [8] and identified genes the 1 Department of Otolaryngology-Head and Neck Surgery, University of expression of which is correlated with corresponding Washington, Seattle, WA 98195, USA Full list of author information is available at the end of the article © 2010 Xu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Common s Attri- bution License (http://creativecommons.org/licenses/by/2.0), whic h permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.