Loss of 3 p 26 . 3 is an independent prognostic factor in patients with oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is a common malignancy worldwide and the prognosis for patients with advanced-stage OSCC is particularly poor. To identify DNA copy number aberrations and candidate genes associated with a poor or favorable outcome, we analyzed the genome profiles of OSCC tumors by array-based comparative genomic hybridization (A-CGH). This technique uses DNA microarray technology to detect genomic copy number variations at a higher resolution level than chromosome-based CGH. Fifty patients with primary OSCCs were included in the study. Of these 50 patients, 37 were treated surgically and 13 were treated without surgery and had received irradiation and/or chemotherapy. All samples were analyzed by A-CGH. Gains were detected frequently (>50%) at chromosomal regions 5p15.33, 7p22.3, 8q21.1-24.3, 9q34.3, 11q13, 16p13.3 and 20q13.3. Losses were frequently detected at 3p22, 3p14 and 4q35.2. High-level gains were recurrently (>10%) detected at each of 5p15, 7p22, 7p11, 8q24, 11q13, 11q22 and 22q11. Gains of 2p25.1, 11p15, 16p13.3, 16q24.3 and 20q13.3 were inversely correlated with nodal metastasis. In 37 of the 50 OSCC patients treated with surgery, gains of 8q12.1-24.22 and losses of 3p26.2-3 were associated with disease-specific survival (p<0.01). Loss of a 0.2 Mb chromosomal region in 3p26.3 was associated with a poor prognostic outcome in the Kaplan-Meier analysis (p<0.01 by the log-rank test). Multivariate analysis revealed that loss of 3p26.3 is an independent prognostic factor (p<0.01) of OSCC. Loss of a 0.2 Mb chromosomal region in 3p26.3 including the CHL1 (cell adhesion molecule with homology to L1CAM1) gene was identified as a novel potential marker for predicting the prognosis of patients with OSCC. Introduction There are approximately 270,000 cases of oral cancer worldwide per year, with deaths exceeding 128,000 (1,2). Most cases of oral cancer involve oral squamous cell carcinoma (OSCC). Diagnostic and therapeutic modalities for OSCC have markedly improved, but the prognosis has not changed significantly for more than two decades and is particularly poor for patients with advanced-stage OSCC (3,4). One of the important prognostic factors of OSCC is nodal metastasis. The biological characteristics of tumors are primarily affected by genetic and epigenetic changes in tumor cells, and identification of genomic alterations underlying malignant behavior of tumors may lead to an improvement of prognosis prediction and anticancer strategies for OSCC patients. The accumulation of genomic aberrations, especially in proto-oncogenes and tumor suppressor genes, plays an important role in carcinogenesis and tumor progression. Comparative genomic hybridization (CGH) is a powerful tool that allows detection of genomic aberrations in a tumor sample in a single experiment (5). We have analyzed OSCCs by conventional (chromosome-based) CGH and identified frequent DNA copy number aberrations (DCNAs) as gains of 3q, 5p, 8q, 12p, 20 and X; and losses of 3p, 4, 8p, 13q, 17p, and 18q (6-10). Loss of heterozygosity (LOH) at 9p, 3p, and 17p as the early event and LOH at 4q, 6p, 8,11q, 13q, and 14q as the late event have been reported in OSCC development (11,12). However, few genes implicated in oral tumorigenesis have been identified in these studies. For example, allelic imbalances of p16 (CDKN2A) and FHIT loci have been associated with these chromosomal alterations and have been implicated in OSCC development (13,14). Array-based CGH (A-CGH), in which DNA microarray technology is used for CGH, has recently been developed and provides high-resolution information at the gene level in genome-wide screenings of DCNAs (15-18). A-CGH makes it possible to detect sufficiently narrow chromosomal regions to allow identification of genes involved in each tumor. DCNAs of clinical OSCC specimens have been investigated in several studies using A-CGH, but a significant association between DCNAs and the prognosis of OSCC patients has been scarcely shown (19-21). In the present study, we applied A-CGH to Loss of 3p26.3 is an independent prognostic factor in patients with oral squamous cell carcinoma KENICHIRO UCHIDA1, ATSUNORI OGA2, MOTONAO NAKAO2, TAKAMITSU MANO1, MARIKO MIHARA1, SHIGETO KAWAUCHI2, TOMOKO FURUYA2, YOSHIYA UEYAMA1 and KOHSUKE SASAKI2 Departments of 1Oral and Maxillofacial Surgery, and 2Pathology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan Received March 26, 2011; Accepted April 28, 2011 DOI: 10.3892/or.2011. 1327 Correspondence to: Dr Kenichiro Uchida, Department of Oral and Maxillofacial Surgery, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan E-mail: k.uchida@yamaguchi-u.ac. jp