癌症一般認為與基因體與外顯基因體發生變異有關，而在外顯基因體研究中，基因啟動子過度甲基化是最主要造成基因不活化的原因。抑癌基因的啟動子過度甲基化，會造成抑癌基因不活化，進而導致癌症的發生，所以在癌症基因體中過度甲基化的區域可能包含有新穎的抑癌基因。因此我們利用差異甲基化雜交法（differential methylation hybridization）的微陣列分析及染色質免疫沈澱晶片分析法（chromatin immunoprecipitation -on -chip） ，針對 20位非小細胞肺癌病人及數個肺癌細胞株進行基因體的過度甲基化區域及染色質鬆緊狀態研究。結果發現在不同的肺癌子類型及肺癌分期，有特定的基因被過度甲基化，這些過度甲基化基因也許可以作為早期偵測及預測癌症發展的生物指標。於肺癌病人的差異甲基化雜交法的結果中，我們發現一個與抗細胞增生、細胞靜止與細胞分化的COL14A1基因啟動子有過度甲基化的情形 ，而且在染色質免疫沈澱晶片分析法中 ，COL14A1啟動子的染色質區域相較於正常肺細胞，肺癌細胞呈現較為緊密的狀態。此外，我們發現有 60.4%的非小細胞肺癌病人有 COL14A1 基因啟動子過度甲基化的情形，而且其 mRNA 及蛋白質分別有50.0%及 43.9%的低表達情形。另外我們也發現 COL14A1基因啟動子過度甲基化與晚期肺癌病人有統計相關。總結，我們利用外顯基因體的分析實驗所找出的肺癌病人過度甲基化基因，可能參與肺癌的形成與進程，未來也許可作為肺癌的生物指標。

Cancer is caused by the accumulation of both genetic and epigenetic changes. Promoter hypermethylation is one of the major epigenetic changes that cause gene inactivation. Aberrant promoter hypermethylation of CpG islands associated with tumor suppressor genes (TSGs) can lead to
transcriptional silencing and result in tumorigenesis. The genomic regions with hypermethylation status may possess novel candidate TSGs. We used a microarray-based epigenome-wide methylation analysis called differential methylation hybridization (DMH) to identify the regions of ypermethylation and a chromatin immunoprecipitation (ChIP)-on-chip analysis to identify the regions of condensed or open chromatin in 20 non-small cell lung cancer (NSCLC) patients and several lung cell lines, and have successfully detected several cancer subtype- and stage-specific hypermethylated genes. They may serve as biomarkers for the early detection or prognosis prediction of lung cancer. Using DMH, we identified promoter hypermethylation of the COL14A1 (collagen, type XIV, alpha 1) gene, which has cell anti-proliferative activity and plays a role in cell quiescence and differentiation. Using ChIP-on-chip, COL14A1 promoter region was shown to be in compact chromatin structure in cancer cell lines. In addition, we found that 60.4% of 48 NSCLC patients showed COL14A1 promoter hypermethylation and coincided with low mRNA and protein expression. Moreover, COL14A1 promoter hypermethylation was significantly associated with late stage lung cancer patients. In conclusion, our study provides the evidence that hypermethylation of specific genes are involved in lung tumor initiation or progression and may serve as tumor biomarkers.