Integrative analysis of DNA copy number and gene expression in metastatic oral squamous cell carcinoma identifies genes associated with poor survival.
BACKGROUND
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.
Xu
Chang
C
Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, WA 98195, USA.
Liu
Yan
Y
Wang
Pei
P
Fan
Wenhong
W
Rue
Tessa C
TC
Upton
Melissa P
MP
Houck
John R
JR
Lohavanichbutr
Pawadee
P
Doody
David R
DR
Futran
Neal D
ND
Zhao
Lue Ping
LP
Schwartz
Stephen M
SM
Chen
Chu
C
Méndez
Eduardo
E
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D016016:Proportional Hazards Models; D012333:RNA, Messenger; D012372:ROC Curve; D055815:Young Adult
D012333:RNA, Messenger