在全世界肺癌是造成癌症致死率很高的首要原因,主要型態包括小細胞肺癌(~15%)與非小細胞肺癌(~85%),非小細胞肺癌又可以分為肺腺癌, 鱗狀上皮細胞肺癌和大細胞肺癌,其中以肺腺癌在台灣佔大多數，在不同類別的肺癌裡，分別都使用不同的化療用藥，造成的副作用與預後情形也都不一樣。分化完全的肺腺癌和鱗狀上皮細胞肺癌通常只需要經由蘇木精和伊紅染色法之後經由肉眼判斷癌細胞型態與角質化與否便能有效辨別腫瘤細胞，但是分化不全的非小細胞肺癌卻很難由肉眼判斷。在病理與臨床應用上，NKX2-1與KRT5/6是目前分別被應用在輔助鑑別分化不全的非小細胞肺癌裡的肺腺癌和鱗狀上皮細胞肺癌上的病理標記。經由研究發現NKX2-1與KRT5/6目前對於在鑑別分化不全之小樣本非小細胞肺癌上效果也並不是相當成功。因此發展出能夠有效鑑別分化不全之小樣本非小細胞肺癌的生物病理標記是當前刻不容緩的研究議題。運用生物資訊與高通量篩選平台及整合功能性生物分析工具並藉由微陣列生物晶片分析及免疫染色法我們最後找出4種生物標記分別為KRT13, ADH7, CALML3和FOXA2來鑑別分化不全之小樣本非小細胞肺癌，希望在病理與臨床應用上，對於非小細胞肺癌診斷、療效評估與化學治療方法的選擇能夠有新的突破。

Lung cancer is the leading cause of cancer deaths in the worldwide. The main tumor type includes small cell lung cancer (SCLC ~15% of all lung cancers) and non-small cell lung cancer (NSCLC ~85% of all lung cancers), NSCLC can be classified in adenocarcinoma (AD), squamous-cell carcinoma (SCC), large-cell lung cancer (LCC). Among them, the majority of lung cancer is AD in Taiwan. The different chemotherapy therapeutic drugs can cause the different side effect and prognosis in different kind of lung cancer. Well differentiated AD and SCC can be identify effectively through tumor type or have cytokeratin or not and poorly differentiated AD and SCC is hardly to distinguish by using Hematoxylin & Eosin immunohistochemistry. In pathology and clinical application, NKX2-1 and KRT5/6 are a biomarker, applied to identify poorly differentiated AD and SCC. It is discovered that NKX2-1 and KRT5/6 identify poorly differentiated AD and SCC not very successfully by some research. Therefore, the development of biomarkers can whether effectively identify small samples of poorly differentiated NSCLC or not is currently pressing research issues. Using biological information and high-throughput platform technology, we found 4 biomarkers, including KRT13, ADH7, CALML and FOXA2, may apply to identify small samples of poorly differentiated AD and SCC. We hope it can raise a possibility for the pathology and clinical aspect in the identification of novel molecular markers for disease diagnosis, prognosis, and therapy selection.

1.Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA: a cancer journal for clinicians 2011, 61(2):69-90.
2.Wang B-Y, Hung J-J, Jeng W-J, Hsu W-H, Hsieh C-C, Huang M-H, Huang B-S, Liu J-S, Wu Y-C: Surgical Outcomes in Resected Non-small Cell Lung Cancer≤ 1 cm in Diameter. Journal of the Chinese Medical Association 2010, 73(6):308-313.
3.Sanchez‐Palencia A, Gomez‐Morales M, Gomez‐Capilla JA, Pedraza V, Boyero L, Rosell R, Fárez‐Vidal M: Gene expression profiling reveals novel biomarkers in nonsmall cell lung cancer. International Journal of Cancer 2011, 129(2):355-364.
4.Lu T-P, Tsai M-H, Lee J-M, Hsu C-P, Chen P-C, Lin C-W, Shih J-Y, Yang P-C, Hsiao CK, Lai L-C: Identification of a Novel Biomarker, SEMA5A, for Non–Small Cell Lung Carcinoma in Nonsmoking Women. Cancer Epidemiology Biomarkers & Prevention 2010, 19(10):2590-2597.
5.Minna JD, Gazdar AF, Sprang SR, Herz J: A bull's eye for targeted lung cancer therapy. Science 2004, 304(5676):1458-1461.
6.Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M: Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proceedings of the National Academy of Sciences 2001, 98(24):13790-13795.
7.Einhorn LH: First-Line Chemotherapy for Non–Small-Cell Lung Cancer: Is There a Superior Regimen Based on Histology? Journal of Clinical Oncology 2008, 26(21):3485-3486.
8.Brown PO, Botstein D: Exploring the new world of the genome with DNA microarrays. Nature genetics 1999, 21:33-37.
9.Su L-J, Chang C-W, Wu Y-C, Chen K-C, Lin C-J, Liang S-C, Lin C-H, Whang-Peng J, Hsu S-L, Chen C-H: Selection of DDX5 as a novel internal control for Q-RT-PCR from microarray data using a block bootstrap re-sampling scheme. BMC genomics 2007, 8(1):140.
10.Kuner R, Muley T, Meister M, Ruschhaupt M, Buness A, Xu EC, Schnabel P, Warth A, Poustka A, Sültmann H: Global gene expression analysis reveals specific patterns of cell junctions in non-small cell lung cancer subtypes. Lung cancer 2009, 63(1):32-38.
11.Shi W, Banerjee A, Ritchie ME, Gerondakis S, Smyth GK: Illumina WG-6 BeadChip strips should be normalized separately. BMC bioinformatics 2009, 10(1):372.
12.Matoso A, Mukkada VA, Lu S, Monahan R, Cleveland K, Noble L, Mangray S, Resnick MB: Expression microarray analysis identifies novel epithelial-derived protein markers in eosinophilic esophagitis. Modern Pathology 2013.
13.de Matos LL, Trufelli DC, de Matos MGL, da Silva Pinhal MA: Immunohistochemistry as an important tool in biomarkers detection and clinical practice. Biomarker insights 2010, 5:9.
14.Tarca AL, Lauria M, Unger M, Bilal E, Boue S, Dey KK, Hoeng J, Koeppl H, Martin F, Meyer P: Strengths and limitations of microarray-based phenotype prediction: Lessons learned from the improver diagnostic signature challenge. Bioinformatics 2013, 29(22):2892-2899.
15.Rousseaux S, Debernardi A, Jacquiau B, Vitte A-L, Vesin A, Nagy-Mignotte H, Moro-Sibilot D, Brichon P-Y, Lantuejoul S, Hainaut P: Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers. Science translational medicine 2013, 5(186):186ra166-186ra166.
16.Der SD, Sykes J, Pintilie M, Zhu C-Q, Strumpf D, Liu N, Jurisica I, Shepherd FA, Tsao M-S: Validation of a Histology-Independent Prognostic Gene Signature for Early-Stage, Non–Small-Cell Lung Cancer Including Stage IA Patients. Journal of Thoracic Oncology 2014, 9(1):59-64.
17.Botling J, Edlund K, Lohr M, Hellwig B, Holmberg L, Lambe M, Berglund A, Ekman S, Bergqvist M, Pontén F: Biomarker discovery in Non–Small cell lung cancer: Integrating gene expression profiling, meta-analysis, and tissue microarray validation. Clinical Cancer Research 2013, 19(1):194-204.
18.Xie Y, Xiao G, Coombes KR, Behrens C, Solis LM, Raso G, Girard L, Erickson HS, Roth J, Heymach JV: Robust Gene Expression Signature from Formalin-Fixed Paraffin-Embedded Samples Predicts Prognosis of Non–Small-Cell Lung Cancer Patients. Clinical Cancer Research 2011, 17(17):5705-5714.
19.Hou J, Aerts J, Den Hamer B, Van Ijcken W, Den Bakker M, Riegman P, van der Leest C, van der Spek P, Foekens JA, Hoogsteden HC: Gene expression-based classification of non-small cell lung carcinomas and survival prediction. PloS one 2010, 5(4):e10312.
20.Irizarry RA, Hobbs B, Collin F, Beazer‐Barclay YD, Antonellis KJ, Scherf U, Speed TP: Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003, 4(2):249-264.
21.Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP: Summaries of Affymetrix GeneChip probe level data. Nucleic acids research 2003, 31(4):e15-e15.
22.Basseres DS, D’Alò F, Yeap BY, Löwenberg EC, Gonzalez DA, Yasuda H, Dayaram T, Kocher ON, Godleski JJ, Richards WG: Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing. Lung cancer 2012, 77(1):31-37.
23.Hamakawa H, Bao Y, Takarada M, Fukuzumi M, Tanioka H: Cytokeratin expression in squamous cell carcinoma of the lung and oral cavity: an immunohistochemical study with possible clinical relevance. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 1998, 85(4):438-443.
24.Shahdoust M, Hajizadeh E, Mozdarani H, Chehrei A: Finding Genes Discriminating Smokers from Non-smokers by Applying a Growing Self-organizing Clustering Method to Large Airway Epithelium Cell Microarray Data. Asian Pacific Journal of Cancer Prevention 2013, 14(1):111-116.