Chen Chu, Méndez Eduardo, Houck John, Fan Wenhong, Lohavanichbutr Pawadee, Doody Dave, Yueh Bevan, Futran Neal D, Upton Melissa, Farwell D Gregory, Schwartz Stephen M, Zhao Lue Ping
Program in Epidemiology, Fred Hutchinson Cancer Research Center, DEpartment of Epidemiology, 1100 Fairview Avenue North, M5-C800 P.O. Box 19024, Seattle, WA 98109-1024, USA.
Cancer Epidemiol Biomarkers Prev. 2008 Aug;17(8):2152-62. doi: 10.1158/1055-9965.EPI-07-2893. Epub 2008 Jul 31.
Oral squamous cell carcinoma (OSCC) is associated with substantial mortality and morbidity. To identify potential biomarkers for the early detection of invasive OSCC, we compared the gene expressions of incident primary OSCC, oral dysplasia, and clinically normal oral tissue from surgical patients without head and neck cancer or preneoplastic oral lesions (controls), using Affymetrix U133 2.0 Plus arrays. We identified 131 differentially expressed probe sets using a training set of 119 OSCC patients and 35 controls. Forward and stepwise logistic regression analyses identified 10 successive combinations of genes which expression differentiated OSCC from controls. The best model included LAMC2, encoding laminin-gamma2 chain, and COL4A1, encoding collagen, type IV alpha1 chain. Subsequent modeling without these two markers showed that COL1A1, encoding collagen, type I alpha1 chain, and PADI1, encoding peptidyl arginine deiminase, type 1, could also distinguish OSCC from controls. We validated these two models using an internal independent testing set of 48 invasive OSCC and 10 controls and an external testing set of 42 head and neck squamous cell carcinoma cases and 14 controls (GEO GSE6791), with sensitivity and specificity above 95%. These two models were also able to distinguish dysplasia (n = 17) from control (n = 35) tissue. Differential expression of these four genes was confirmed by quantitative reverse transcription-PCR. If confirmed in larger studies, the proposed models may hold promise for monitoring local recurrence at surgical margins and the development of second primary oral cancer in patients with OSCC.
口腔鳞状细胞癌（OSCC）与较高的死亡率和发病率相关。为了确定早期检测侵袭性OSCC的潜在生物标志物，我们使用Affymetrix U133 2.0 Plus芯片，比较了初发原发性OSCC、口腔发育异常以及来自无头颈癌或癌前口腔病变的手术患者（对照组）的临床正常口腔组织的基因表达。我们使用由119例OSCC患者和35例对照组成的训练集，鉴定出131个差异表达的探针集。向前和逐步逻辑回归分析确定了10个连续的基因组合，其表达可区分OSCC与对照。最佳模型包括编码层粘连蛋白γ2链的LAMC2和编码IV型胶原α1链的COL4A1。随后在没有这两个标志物的情况下进行建模显示，编码I型胶原α1链的COL1A1和编码1型肽基精氨酸脱亚氨酶的PADI1也可区分OSCC与对照。我们使用48例侵袭性OSCC和10例对照的内部独立测试集以及42例头颈鳞状细胞癌病例和14例对照的外部测试集（GEO GSE6791）验证了这两个模型，其敏感性和特异性均高于95%。这两个模型还能够区分发育异常组织（n = 17）与对照组织（n = 35）。通过定量逆转录PCR证实了这四个基因的差异表达。如果在更大规模的研究中得到证实，所提出的模型可能有望用于监测OSCC患者手术切缘的局部复发以及第二原发性口腔癌的发生。
