口腔癌是台灣男性十大常見癌症的第四位，死亡率亦逐年增加。流行病學研究顯示抽菸、飲酒及嚼食檳榔是台灣地區口腔癌的主要危險因子。本論文以口腔癌個案之危險暴露因子為選樣依據，分別運用微衛星序列標記組及兩種單一核苷酸多形性微陣列晶片平台（SNP 500K及SNP 6.0）進行口腔癌腫瘤組織全基因體失去異合性及染色體套數變異分析，來探討台灣地區男性口腔鱗狀上皮細胞癌基因體變異概覽。利用400個微衛星序列標記分析63個男性口腔癌腫瘤基因體，歸納出32個最小缺失區段(minimally deleted region, MDR)。其中有六個MDR與個案抽菸習慣有關，腫瘤組織在其中一個MDR c7r2 (7q32.2-q35)區段有缺失的口腔癌個案，其無病存活率較差（p值為0.046）。，此外，發現10個MDR與對偶基因失衡（allelic imbalance, AI）指數具統計顯著相關性，其中的MDR c14r1 (14q24.2-q32.12)及c11r1 (11q13.4-q25)的缺失會協同降低個案的無病存活率（p值為0.004）；而同時MDR c7r2的缺失會再度降低個案的無病存活率（p值為0.001）。
利用500K及SNP 6.0單一核苷酸多形性微陣列晶片分別分析26個及46個晚期口腔癌腫瘤組織染色體之套數變異情形，並以GISTIC分析法訂出套數變異屬非隨機之區段(FDR q-value < 0.25)。500K平台歸納出46個非隨機套數變異區段（14個套數增加與32個套數遺失區段）；SNP 6.0平台獲得208個非隨機套數變異區段（48個套數增加與160個套數減少區段）。兩平台所顯示的共同區段有15個，分別為8個套數增加區段(3q26.1、7p11.2、11q13.3、13q22.1、15q11.2、17p13.3、18p11.23-p11.31及20p11.22)及7個套數遺失區段(1q21.1、6p21.33、7q31.3、12q14.1、14q11.2及15q11.2)；其中與淋巴結轉移達統計顯著水準的變異區段為3q26.1及18p11.23-p11.31與15q11.2 （p值分別為0.029、0.030、0.021）；與口腔癌個案預後達統計顯著水準的變異區段為14q11.2。進一步分別以CCND1及EGFR探針進行螢光原位雜交驗證其所歸屬之11q13.3及7p11.2套數變異，發現其一致性為0.82與0.79。
結論：本論文以全基因體微衛星序列標記失去異合性及單一核苷酸多形性微陣列晶片分析染色體套數變異初步歸納出台灣地區抽菸及嚼食檳榔致口腔癌之基因體變異特徵，有助於未來明晰台灣地區男性口腔癌之致病基因。

In Taiwan, oral cancer is the fourth leading cause of cancer death in men. The motality rate is still rising. Epidemiological studies have indicated that cigarette smoking, alcohol drinking and areca quid chewing are the major risk factors. In the present study, we used microsatellite markers and SNP array to explore the genomic aberration profiles of male oral cavity squamous cell carcinoma (OSCC) in Taiwan with a study design upon patient’s history of cigarette smoking and areca quid chewing. A systematic loss of heterozygosity (LOH) analysis was performed to define 32 minimally deleted regions (MDRs) in 63 male OSCCs using 400 polymorphic microsatellite markers. Six MDRs were found to be associated with cigarette smoking. Among these markers, a loss of MDR c7r2 (7q32.2-q35) was significantly associated with poor disease-free survival (DFS, p=0.046) and ten MDRs were associated with allelic imbalance (AI) in tumors. Among the latter, a loss of MDR c14r1 (14q24.2-q32.12) and c11r1 (11q13.4-q25) had a synergistic effect on poor DFS (p=0.004) and were able to reduce further the DFS rate in patients with MDR c7r2 loss (p=0.001). Seventy-two advanced-stage OSCCs were analysed using two microarray platforms (26 cases with Affymetrix SNP 500K and 46 cases with Affymetrix SNP 6.0) to identify regions for copy number alterations (CNAs). GISTIC (genomic identification of significant targets in cancer) was further applied to determine the regions which were not random event (FDR q-value <0.25). With this approach, 46 (14 gain and 32 loss) and 208 (48 gain and 160 loss) non-random regions were identified from 500K and SNP 6.0 plateform, respectively. Among them, 15 focal CNAs (8 gains (3q26.1, 7p11.2, 11q13.3, 13q22.1, 15q11.2, 17p13.3, 18p11.23-p11.31, and 20p11.22) and 7 losses (1q21.1, 6p21.33, 7q31.3, 12q14.1, 2 focal regions in 14q11.2, 15q11.2)) were common in these 2 plateforms. The clinicopathologic significances of these 15 CNAs were examined. Gain of 3q26.1 and 18p11.23-p11.31, and loss of 15q11.2 were correlated significantly with lymph node metastasis (p=0.029, 0.030, 0.021, respectively). Loss of two focal regions in 14q11.2 was significantly associated with disease- free and overall survival. Furthermore, amplification of 11q13.3 and 7p11.2 containing known oncogenes CCND1 and EGFR were confirmed by fluorescence in situ hybridization (FISH) with high concordance rate.
In conclusion, the results of whole-genome LOH and CNAs analysis provide useful clues for future exploring the pathogenic genes associated with OSCC tumorgenesis in Tawian.

目 錄
長庚大學博士學位論文指導教授推薦書
長庚大學博士學位論文口試委員會審定書
長庚大學博士論文著作授權書 - iii -
誌謝 - iv -
中文摘要 - v -
英文摘要 - vii -
目錄 - ix -
表目錄 - x -
圖目錄 - xii -
第一章 緒論 - 1 -
1.1 前言 - 1 -
1.2 口腔癌的流行病學特徵 - 2 -
1.3基因變異與基因體不穩定 - 4 -
1.4染色體不穩定 - 6 -
1.5抽菸及嚼食檳榔致口腔癌之相關研究 - 10 -
1.6口腔癌基因體變異研究 - 14 -
第二章 研究目的 - 21 -
第三章 研究材料與方法 - 22 -
3.1研究個案 - 24 -
3.2實驗方法 - 26 -
3.3資料分析 - 46 -
第四章 研究結果 - 48 -
4.1微衛星序列標記分析口腔癌腫瘤基因體失去異合性 - 48 -
4.2腫瘤組織最小缺失區段候選基因失去異合性分析 - 55 -
4.3 GeneChip® Human Mapping 500K Array口腔癌腫瘤組
織基因體套數變異分析 - 59 -
4.4 Affymetrix® Genome-Wide Human SNP Array 6.0口腔
癌腫瘤組織基因體套數變異分析 - 61 -
4.5 500K array及SNP 6.0兩平台口腔癌腫瘤組織共同非隨
機套數變異區段分析 - 63 -
4.6口腔癌腫瘤組織染色體套數變異區段候選標的腫瘤基
因分析 - 64 -
第五章 討論 - 67 -
5.1口腔癌腫瘤組織基因體微衛星序列標記失去異合性概
觀 - 67 -
5.2台灣地區男性口腔鱗狀上皮細胞癌全基因體套數變異
分析 - 74 -
第六章 結論 - 84 -
參考文獻 - 158 -


表目錄
表1 微衛星序列失去異合性分析之口腔癌個案臨床基本特徵 - 91 -
表2 以500K或SNP 6.0微陣列晶片分析之口腔癌個案臨床
基本特徵 - 92 -
表3 以候選標的基因進行失去異合性分析之口腔癌個案臨床
基本特徵 - 93 -
表4 口腔癌腫瘤基因體失去異合性與臨床病理變項達統計顯
著水準之微衛星序列標記 - 94 -
表5 口腔癌腫瘤基因體失去異合性與口腔癌危險因子達統計
顯著水準之微衛星序列標記 - 97 -
表6 口腔癌腫瘤基因體微衛星序列標記失去異合性分析之最
小缺失區段(minimally deleted region,MDR) - 98 -
表7 口腔癌腫瘤基因體微衛星序列標記失去異合性分析中與
對偶基因失衡(allelic imbalance, AI)指數具統計顯著相關性之
最小缺失區段 - 101 -
表8 口腔癌腫瘤基因體微衛星序列標記失去異合性分析中與
染色體不穩定(chromosomal instability,CIN)具統計顯著相關性
之最小缺失區段 - 102 -
表9 口腔癌腫瘤基因體微衛星序列標記失去異合性分析中與
口腔癌危險因子具統計顯著相關性之最小缺失區段 - 103 -
表10 口腔癌腫瘤基因體微衛星序列標記失去異合性分析中與
口腔癌臨床病理特徵具統計顯著相關性之最小缺失區段 - 104 -
表11 口腔癌染色體不穩定與個案無病存活率之Cox多變項迴
歸分析 - 105 -
表12 口腔癌腫瘤基因MDR缺失與個案無病存活率聯合效應
之Cox單變項迴歸分析 - 106 -
表13 口腔癌腫瘤基因體MDR缺失與對個案無病存活率之
Cox多變項迴歸分析 - 107 -
表14 口腔癌腫瘤組織FOXN3基因失去異合性與個案預後之
相關性 - 108 -
表15 500K微陣列晶片分析口腔癌腫瘤組織染色體套數增加
(gain)屬非隨機之區段 - 109 -
表16 500K微陣列晶片分析口腔癌腫瘤組織染色體套數遺失
(loss)屬非隨機之區段 - 111 -
表17 SNP 6.0微陣列晶片分析口腔癌腫瘤組織染色體套數增
加(gain)屬非隨機之區段 - 113 -
表18 SNP 6.0微陣列晶片分析口腔癌腫瘤組織染色體套數遺
失(loss)屬非隨機之區段 - 117 -
表19 500K及SNP6.0微陣列晶片二平台分析口腔癌腫瘤組織
染色體套數變異達統計顯著水準之共同區段 - 127 -
表20口腔癌腫瘤組織染色體套數變異與臨床病理變項達統計
顯著水準之區段 - 128 -
表21口腔癌腫瘤組織染色體14q11.2區段套數變異與個案存
活率之Cox多變項迴歸分析 - 129 -
表22 微陣列晶片分析染色體11q13.2區段之基因套數與FISH
偵測CCND1基因套數之一致性(N=62) - 130 -
表23 微陣列晶片分析7p11.2區段之基因套數與FISH偵測
EGFR基因套數之一致性(N=52) - 131 -


圖目錄
圖1 口腔癌腫瘤組織微衛星序列標記失去異合性之頻率二相
分布圖 - 132 -
圖2 以高解析熔解曲線分析法(HRM analysis)鑑別基因型及失
去異合性代表圖 - 133 -
圖3 利用引子延展法(primer extension)暨解離式高效能液相層
析儀(denaturing high performance liquid chromatography, DHPLC)
分析標的基因失去異合性之代表圖 - 134 -
圖4 以Vysis公司之CCND1探針進行FISH分析11q13.2區
段之染色體套數代表圖 - 135 -
圖5 口腔癌腫瘤組織微衛星序列標記分析各染色體臂失去異
合性頻率 - 136 -
圖6 口腔癌腫瘤基因體微衛星序列標記分析對偶基因失衡指
數(AI index)分布圖 - 137 -
圖7口腔癌腫瘤組織微衛星序列標記失去異合性分析之最小缺
失區段(MDR) - 138 -
圖8 口腔癌腫瘤基因體微衛星序列標記失去異合性分析之MDR
分布圖 - 139 -
圖9 口腔癌腫瘤組織在微衛星序列標記失去異合性分析之最
小缺失區段發生缺失之區段數分布圖 - 140 -
圖10 口腔癌微衛星序列標記失去異合性分析之對偶基因失衡
與個案無病存活率之相關性 - 141 -
圖11 口腔癌微衛星序列標記失去異合性分析之最小缺失區段
與個案無病存活率之相關性 - 142 -
圖12 口腔癌微衛星序列標記失去異合性分析之單一MDR區
段內單一標記失去異合性與個案無病存活率之相關性 - 143 -
圖13 口腔癌微衛星序列標記失去異合性分析之雙MDR區段
內標記與失去異合性個案無病存活率之相關性 - 144 -
圖14 口腔癌腫瘤組織FOXN3基因失去異合性與臨床預後之
相關性 - 145 -
圖15 500K微陣列晶片分析之口腔癌腫瘤組織各染色體套數變
異片段分布圖(N=26) - 146 -
圖16 500K微陣列晶片分析之口腔癌腫瘤組織各染色體套數變
異頻率(A:套數增加; B:套數遺失) (N=26) - 147 -
圖17 500K微陣列晶片分析之口腔癌腫瘤組織各染色體log2 ratio
分布圖 - 148 -
圖18 口腔癌500K微陣列晶片分析之腫瘤組織各染色體套數
增加屬非隨機之區段 - 149 -
圖19 口腔癌500K微陣列晶片分析之腫瘤組織各染色體套數
遺失屬非隨機之區段 - 150 -
圖20 SNP 6.0微陣列晶片分析之口腔癌腫瘤組織各染色體套數
變異片段分布圖(N=46) - 151 -
圖21 SNP 6.0微陣列晶片分析之口腔癌腫瘤組織各染色體套數
變異頻率(A:套數增加; B:套數遺失) (N=46) - 152 -
圖22 SNP 6.0微陣列晶片分析之口腔癌腫瘤組織各染色體log2 ratio分布圖 - 153 -
圖23口腔癌SNP 6.0微陣列晶片分析之腫瘤組織各染色體套
數增加屬非隨機之區段 - 154 -
圖24口腔癌SNP 6.0微陣列晶片分析之腫瘤組織各染色體套
數遺失屬非隨機之區段 - 155 -
圖25口腔癌腫瘤組織14q11.2(a,b)區段遺失染色體套數變異
與個案存活率分析 - 156 -
圖26口腔癌腫瘤組織染色體套數變異區之基因參與腫瘤特異
訊息路徑KEGG pathway in cancer之分析圖 - 157 -

參考文獻
1. Gupta, P.C., J.J. Pindborg, and F.S. Mehta, Comparison of carcinogenicity of betel quid with and without tobacco: an epidemiological review. Ecol Dis, 1982. 1(4): p. 213-9.
2. Muir, C. and L. Weiland, Upper aerodigestive tract cancers. Cancer, 1995. 75(1 Suppl): p. 147-53.
3. Weinberg, R.A., Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. Cancer Res, 1989. 49(14): p. 3713-21.
4. Lasko, D., W. Cavenee, and M. Nordenskjold, Loss of constitutional heterozygosity in human cancer. Annu Rev Genet, 1991. 25: p. 281-314.
5. Parkin, D.M., P. Pisani, and J. Ferlay, Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer, 1993. 54(4): p. 594-606.
6. Thomas, S.J. and R. MacLennan, Slaked lime and betel nut cancer in Papua New Guinea. Lancet, 1992. 340(8819): p. 577-8.
7. Ko, Y.C., et al., Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. Journal of Oral Pathology & Medicine, 1995. 24(10): p. 450-3.
8. Lengauer, C., K.W. Kinzler, and B. Vogelstein, Genetic instabilities in human cancers. Nature, 1998. 396(6712): p. 643-9.
9. Almoguera, C., et al., Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell, 1988. 53(4): p. 549-54.
10. Ibrahim, S.O., et al., Mutations of the p53 gene in oral squamous-cell carcinomas from Sudanese dippers of nitrosamine-rich toombak and non-snuff-dippers from the Sudan and Scandinavia. International Journal of Cancer, 1999. 81(4): p. 527-34.
11. Pegram, M.D., et al., Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. Journal of Clinical Oncology, 1998. 16(8): p. 2659-71.
12. Seeger, R.C., et al., Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. New England Journal of Medicine, 1985. 313(18): p. 1111-6.
13. Wang, S.I., et al., Somatic mutations of PTEN in glioblastoma multiforme. Cancer Research, 1997. 57(19): p. 4183-6.
14. Zhuang, Z., et al., Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nature Genetics, 1998. 20(1): p. 66-9.
15. Nowell, P.C., Genetic alterations in leukemias and lymphomas: impressive progress and continuing complexity. Cancer Genetics & Cytogenetics, 1997. 94(1): p. 13-9.
16. Girard, L., et al., Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res, 2000. 60(17): p. 4894-906.
17. Schar, P., Spontaneous DNA damage, genome instability, and cancer--when DNA replication escapes control. Cell, 2001. 104(3): p. 329-32.
18. Bayani, J., et al., Genomic mechanisms and measurement of structural and numerical instability in cancer cells. Semin Cancer Biol, 2007. 17(1): p. 5-18.
19. Draviam, V.M., S. Xie, and P.K. Sorger, Chromosome segregation and genomic stability. Curr Opin Genet Dev, 2004. 14(2): p. 120-5.
20. Aguilera, A. and B. Gomez-Gonzalez, Genome instability: a mechanistic view of its causes and consequences. Nat Rev Genet, 2008. 9(3): p. 204-17.
21. Durkin, S.G. and T.W. Glover, Chromosome fragile sites. Annu Rev Genet, 2007. 41: p. 169-92.
22. Knudson, A.G., Jr., Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A, 1971. 68(4): p. 820-3.
23. Cavenee, W.K., et al., Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature, 1983. 305(5937): p. 779-84.
24. Dunn, J.M., et al., Identification of germline and somatic mutations affecting the retinoblastoma gene. Science, 1988. 241(4874): p. 1797-800.
25. Murthy, S.K., et al., Loss of heterozygosity associated with uniparental disomy in breast carcinoma. Mod Pathol, 2002. 15(12): p. 1241-50.
26. Raghavan, M., et al., Genome-wide single nucleotide polymorphism analysis reveals frequent partial uniparental disomy due to somatic recombination in acute myeloid leukemias. Cancer Res, 2005. 65(2): p. 375-8.
27. Teh, M.T., et al., Genomewide single nucleotide polymorphism microarray mapping in basal cell carcinomas unveils uniparental disomy as a key somatic event. Cancer Res, 2005. 65(19): p. 8597-603.
28. Maier, H., et al., Tobacco and alcohol and the risk of head and neck cancer. Clin Investig, 1992. 70(3-4): p. 320-7.
29. Vokes, E.E., et al., Head and neck cancer. N Engl J Med, 1993. 328(3): p. 184-94.
30. WHO, IARC Monographs on the evaluation of carcinogenic risk of chemicals in human. Vol. 37. 1985, Lyon: IARC.
31. 行政院農業委員會, 九十一年農業統計年報, 行政院農業委員會: 台北市.
32. Hoffmann, D. and S.S. Hecht, Nicotine-derived N-nitrosamines and tobacco-related cancer: current status and future directions. Cancer Res, 1985. 45(3): p. 935-44.
33. Canniff, J.P., W. Harvey, and M. Harris, Oral submucous fibrosis: its pathogenesis and management. Br Dent J, 1986. 160(12): p. 429-34.
34. Meghji, S., M.F. Haque, and M. Harris, Oral submucous fibrosis and copper. Lancet, 1997. 350(9072): p. 220.
35. Pillai, R., P. Balaram, and K.S. Reddiar, Pathogenesis of oral submucous fibrosis. Relationship to risk factors associated with oral cancer. Cancer, 1992. 69(8): p. 2011-20.
36. Sen, S., G. Talukder, and A. Sharma, Betel cytotoxicity. J Ethnopharmacol, 1989. 26(3): p. 217-47.
37. Chen, C.C., J.F. Huang, and C.C. Tsai, In vitro production of interleukin-6 by human gingival, normal buccal mucosa, and oral submucous fibrosis fibroblasts treated with betel-nut alkaloids. Gaoxiong Yi Xue Ke Xue Za Zhi, 1995. 11(11): p. 604-14.
38. Chang, J.T., et al., Identification of differentially expressed genes in oral squamous cell carcinoma (OSCC): overexpression of NPM, CDK1 and NDRG1 and underexpression of CHES1. Int J Cancer, 2005. 114(6): p. 942-9.
39. Tang, D.W., et al., Elevated expression of cyclooxygenase (COX)-2 in oral squamous cell carcinoma--evidence for COX-2 induction by areca quid ingredients in oral keratinocytes. J Oral Pathol Med, 2003. 32(9): p. 522-9.
40. Chan, G., et al., Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res, 1999. 59(5): p. 991-4.
41. Dave, B.J., A.H. Trivedi, and S.G. Adhvaryu, In vitro genotoxic effects of areca nut extract and arecoline. J Cancer Res Clin Oncol, 1992. 118(4): p. 283-8.
42. Jeng, J.H., et al., Effects of areca nut, inflorescence piper betle extracts and arecoline on cytotoxicity, total and unscheduled DNA synthesis in cultured gingival keratinocytes. J Oral Pathol Med, 1999. 28(2): p. 64-71.
43. Jeng, J.H., et al., Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro. J Dent Res, 1994. 73(5): p. 1043-9.
44. Sundqvist, K., et al., Cytotoxic and genotoxic effects of areca nut-related compounds in cultured human buccal epithelial cells. Cancer Res, 1989. 49(19): p. 5294-8.
45. Stich, H.F. and F. Anders, The involvement of reactive oxygen species in oral cancers of betel quid/tobacco chewers. Mutat Res, 1989. 214(1): p. 47-61.
46. Nair, U.J., et al., Effect of lime composition on the formation of reactive oxygen species from areca nut extract in vitro. Carcinogenesis, 1990. 11(12): p. 2145-8.
47. Hwang L.S., W.C.K., Sheu M.J., Kao L.S., Phenoliccompounds of piper betel flower as flavoring and nuronal activity modulating agents, in Food Phytochemicals for Cancer Prevention I, O.T. Ho C.T., Huang M.T., Rossen R.T., Editor. 1994, American Chemical Society: Washington, DC. p. 186-191.
48. Miller, J.A. and E.C. Miller, The metabolic activation and nucleic acid adducts of naturally-occurring carcinogens: recent results with ethyl carbamate and the spice flavors safrole and estragole. Br J Cancer, 1983. 48(1): p. 1-15.
49. Abou-Elhamd, K.E., et al., The role of genetic susceptibility in head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol, 2008. 265(2): p. 217-22.
50. Shen, C.Y., et al., Genome-wide search for loss of heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator phenotype and breast cancer pathogenesis. Cancer Research, 2000. 60(14): p. 3884-92.
51. Iacobuzio-Donahue, C.A., et al., Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss. Cancer Res, 2004. 64(3): p. 871-5.
52. Tseng, R.C., et al., Genomewide loss of heterozygosity and its clinical associations in non small cell lung cancer. Int J Cancer, 2005. 117(2): p. 241-7.
53. Ah-See, K.W., et al., An allelotype of squamous carcinoma of the head and neck using microsatellite markers. Cancer Research, 1994. 54(7): p. 1617-21.
54. Beder, L.B., et al., Genome-wide analyses on loss of heterozygosity in head and neck squamous cell carcinomas. Laboratory Investigation, 2003. 83(1): p. 99-105.
55. Field, J.K., et al., Allelotype of squamous cell carcinoma of the head and neck: fractional allele loss correlates with survival. British Journal of Cancer, 1995. 72(5): p. 1180-8.
56. Nawroz, H., et al., Allelotype of head and neck squamous cell carcinoma. Cancer Research, 1994. 54(5): p. 1152-5.
57. Huebner, K. and C.M. Croce, Cancer and the FRA3B/FHIT fragile locus: it's a HIT. Br J Cancer, 2003. 88(10): p. 1501-6.
58. Pavelic, K., et al., Aberration of FHIT gene is associated with increased tumor proliferation and decreased apoptosis-clinical evidence in lung and head and neck carcinomas. Mol Med, 2001. 7(7): p. 442-53.
59. Hogg, R.P., et al., Frequent 3p allele loss and epigenetic inactivation of the RASSF1A tumour suppressor gene from region 3p21.3 in head and neck squamous cell carcinoma. Eur J Cancer, 2002. 38(12): p. 1585-92.
60. Jiang, W.W., et al., Accumulative increase of loss of heterozygosity from leukoplakia to foci of early cancerization in leukoplakia of the oral cavity. Cancer, 2001. 92(9): p. 2349-56.
61. Gonzalez, M.V., et al., Deletion and methylation of the tumour suppressor gene p16/CDKN2 in primary head and neck squamous cell carcinoma. Journal of Clinical Pathology, 1997. 50(6): p. 509-12.
62. Califano, J., et al., Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Research, 1996. 56(11): p. 2488-92.
63. Jin, Y., et al., FISH characterization of head and neck carcinomas reveals that amplification of band 11q13 is associated with deletion of distal 11q. Genes Chromosomes Cancer, 1998. 22(4): p. 312-20.
64. Jin, C., et al., Molecular cytogenetic characterization of the 11q13 amplicon in head and neck squamous cell carcinoma. Cytogenet Genome Res, 2006. 115(2): p. 99-106.
65. Maestro, R., et al., Chromosome 13q deletion mapping in head and neck squamous cell carcinomas: identification of two distinct regions of preferential loss. Cancer Res, 1996. 56(5): p. 1146-50.
66. Andl, T., et al., Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control. Cancer Res, 1998. 58(1): p. 5-13.
67. Gunduz, M., et al., Genomic structure of the human ING1 gene and tumor-specific mutations detected in head and neck squamous cell carcinomas. Cancer Res, 2000. 60(12): p. 3143-6.
68. Sanchez-Cespedes, M., et al., Molecular analysis of the candidate tumor suppressor gene ING1 in human head and neck tumors with 13q deletions. Genes Chromosomes Cancer, 2000. 27(3): p. 319-22.
69. Li, X., K. Kikuchi, and Y. Takano, ING Genes Work as Tumor Suppressor Genes in the Carcinogenesis of Head and Neck Squamous Cell Carcinoma. J Oncol, 2011. 2011: p. 963614.
70. Carlos de Vicente, J., et al., Prognostic significance of p53 expression in oral squamous cell carcinoma without neck node metastases. Head Neck, 2004. 26(1): p. 22-30.
71. Scully, C., J.K. Field, and H. Tanzawa, Genetic aberrations in oral or head and neck squamous cell carcinoma 2: chromosomal aberrations. Oral Oncol, 2000. 36(4): p. 311-27.
72. Tong, B.C., et al., Use of single nucleotide polymorphism arrays to identify a novel region of loss on chromosome 6q in squamous cell carcinomas of the oral cavity. Head Neck, 2004. 26(4): p. 345-52.
73. Zhou, X., et al., Whole genome loss of heterozygosity profiling on oral squamous cell carcinoma by high-density single nucleotide polymorphic allele (SNP) array. Cancer Genet Cytogenet, 2004. 151(1): p. 82-4.
74. Zhou, X., et al., Concurrent analysis of loss of heterozygosity (LOH) and copy number abnormality (CNA) for oral premalignancy progression using the Affymetrix 10K SNP mapping array. Hum Genet, 2004. 115(4): p. 327-30.
75. Zhou, X., et al., Progress in concurrent analysis of loss of heterozygosity and comparative genomic hybridization utilizing high density single nucleotide polymorphism arrays. Cancer Genet Cytogenet, 2005. 159(1): p. 53-7.
76. Beroukhim, R., et al., Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc Natl Acad Sci U S A, 2007. 104(50): p. 20007-12.
77. Teh, M.T., et al., Fingerprinting genomic instability in oral submucous fibrosis. J Oral Pathol Med, 2008. 37(7): p. 430-6.
78. Xu, C., et al., Integrative analysis of DNA copy number and gene expression in metastatic oral squamous cell carcinoma identifies genes associated with poor survival. Mol Cancer, 2010. 9: p. 143.
79. Peng, C.H., et al., A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma. PLoS One, 2011. 6(8): p. e23452.
80. Emmert-Buck, M.R., et al., Laser capture microdissection. Science, 1996. 274(5289): p. 998-1001.
81. Bonner, R.F., et al., Laser capture microdissection: molecular analysis of tissue. Science, 1997. 278(5342): p. 1481,1483.
82. Thiagalingam, S., et al., Loss of heterozygosity as a predictor to map tumor suppressor genes in cancer: molecular basis of its occurrence. Curr Opin Oncol, 2002. 14(1): p. 65-72.
83. Jou, Y.S., et al., Clustering of minimal deleted regions reveals distinct genetic pathways of human hepatocellular carcinoma. Cancer Res, 2004. 64(9): p. 3030-6.
84. Gorringe, K.L., et al., Mutation and methylation analysis of the chromodomain-helicase-DNA binding 5 gene in ovarian cancer. Neoplasia, 2008. 10(11): p. 1253-8.
85. Hsieh, L.L., et al., p53 polymorphisms associated with mutations in and loss of heterozygosity of the p53 gene in male oral squamous cell carcinomas in Taiwan. Br J Cancer, 2005. 92(1): p. 30-5.
86. Hirsch, F.R., et al., Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol, 2005. 23(28): p. 6838-45.
87. Cappuzzo, F., et al., Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst, 2005. 97(9): p. 643-55.
88. Weber, F., et al., Microenvironmental genomic alterations and clinicopathological behavior in head and neck squamous cell carcinoma. JAMA, 2007. 297(2): p. 187-95.
89. Tsantoulis, P.K., et al., Advances in the biology of oral cancer. Oral Oncol, 2007. 43(6): p. 523-34.
90. Glavac, D., et al., Low microsatellite instability and high loss of heterozygosity rates indicate dominant role of the suppressor pathway in squamous cell carcinoma of head and neck and loss of heterozygosity of 11q14.3 correlates with tumor grade. Cancer Genet Cytogenet, 2003. 146(1): p. 27-32.
91. Rutherford, S., et al., Chromosome 6 deletion and candidate tumor suppressor genes in adenoid cystic carcinoma. Cancer Lett, 2006. 236(2): p. 309-17.
92. Chen, Y. and C. Chen, DNA copy number variation and loss of heterozygosity in relation to recurrence of and survival from head and neck squamous cell carcinoma: a review. Head Neck, 2008. 30(10): p. 1361-83.
93. De Schutter, H., et al., The clinical relevance of microsatellite alterations in head and neck squamous cell carcinoma: a critical review. Eur J Hum Genet, 2007. 15(7): p. 734-41.
94. Takebayashi, S., et al., Loss of chromosome arm 18q with tumor progression in head and neck squamous cancer. Genes Chromosomes Cancer, 2004. 41(2): p. 145-54.
95. Qiu, W., et al., A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma. Oncogene, 2006. 25(20): p. 2937-42.
96. Poli-Frederico, R.C., et al., Chromosome 22q a frequent site of allele loss in head and neck carcinoma. Head Neck, 2000. 22(6): p. 585-90.
97. Xu, S.F., et al., Refinement of heterozygosity loss on chromosome 5p15 in sporadic colorectal cancer. World J Gastroenterol, 2003. 9(8): p. 1713-8.
98. Bisgaard, M.L., et al., Allelic loss of chromosome 2p21-16.3 is associated with reduced survival in sporadic colorectal cancer. Scand J Gastroenterol, 2001. 36(4): p. 405-9.
99. Kozlowski, L., et al., Loss of heterozygosity on chromosomes 2p, 3p, 18q21.3 and 11p15.5 as a poor prognostic factor in stage II and III (FIGO) cervical cancer treated by radiotherapy. Neoplasma, 2006. 53(5): p. 440-3.
100. Li, S.P., et al., Genome-wide analyses on loss of heterozygosity in hepatocellular carcinoma in Southern China. J Hepatol, 2001. 34(6): p. 840-9.
101. Bohm, M., R. Kleine-Besten, and I. Wieland, Loss of heterozygosity analysis on chromosome 5p defines 5p13-12 as the critical region involved in tumor progression of bladder carcinomas. Int J Cancer, 2000. 89(2): p. 194-7.
102. Shin, J.H., et al., Identification of tumor suppressor loci on the long arm of chromosome 5 in pulmonary large cell neuroendocrine carcinoma. Chest, 2005. 128(4): p. 2999-3003.
103. Bicher, A., et al., Loss of heterozygosity in human ovarian cancer on chromosome 19q. Gynecol Oncol, 1997. 66(1): p. 36-40.
104. Ulivieri, A., et al., Frizzled-1 is down-regulated in follicular thyroid tumours and modulates growth and invasiveness. J Pathol, 2008. 215(1): p. 87-96.
105. Haddad, R.I. and D.M. Shin, Recent advances in head and neck cancer. N Engl J Med, 2008. 359(11): p. 1143-54.
106. Feng, W., et al., Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation. Cancer, 2008. 112(7): p. 1489-502.
107. Relaix, F., et al., Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. Proc Natl Acad Sci U S A, 2000. 97(5): p. 2105-10.
108. Lu, R., H. Niida, and M. Nakanishi, Human SAD1 kinase is involved in UV-induced DNA damage checkpoint function. J Biol Chem, 2004. 279(30): p. 31164-70.
109. Graner, M.W., et al., Heat shock protein 70-binding protein 1 is highly expressed in high-grade gliomas, interacts with multiple heat shock protein 70 family members, and specifically binds brain tumor cell surfaces. Cancer Sci, 2009. 100(10): p. 1870-9.
110. Souza, A.P., et al., HspBP1 levels are elevated in breast tumor tissue and inversely related to tumor aggressiveness. Cell Stress Chaperones, 2009. 14(3): p. 301-10.
111. Tryndyak, V.P., O. Kovalchuk, and I.P. Pogribny, Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4-20h2 histone methyltransferase and methyl-binding proteins. Cancer Biol Ther, 2006. 5(1): p. 65-70.
112. Van Den Broeck, A., et al., Loss of histone H4K20 trimethylation occurs in preneoplasia and influences prognosis of non-small cell lung cancer. Clin Cancer Res, 2008. 14(22): p. 7237-45.
113. Tan, G., et al., Microsatellite analyses of loci at 7q31.3-q36 reveal a minimum of two common regions of deletion in nasopharyngeal carcinoma. Otolaryngol Head Neck Surg, 2002. 126(3): p. 296-300.
114. Grati, F.R., et al., Losses of heterozygosity in oral and oropharyngeal epithelial carcinomas. Cancer Genet Cytogenet, 2000. 118(1): p. 57-61.
115. Wang, G., W. Mao, and S. Zheng, MicroRNA-183 regulates Ezrin expression in lung cancer cells. FEBS Lett, 2008. 582(25-26): p. 3663-8.
116. Tavazoie, S.F., et al., Endogenous human microRNAs that suppress breast cancer metastasis. Nature, 2008. 451(7175): p. 147-52.
117. Yu, J., et al., The EPHB6 receptor tyrosine kinase is a metastasis suppressor that is frequently silenced by promoter DNA hypermethylation in non-small cell lung cancer. Clin Cancer Res, 2010. 16(8): p. 2275-83.
118. Fox, B.P. and R.P. Kandpal, EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells. Oncogene, 2009. 28(14): p. 1706-13.
119. Pehlivan, D., et al., Loss of heterozygosity at chromosome 14q is associated with poor prognosis in head and neck squamous cell carcinomas. J Cancer Res Clin Oncol, 2008. 134(12): p. 1267-76.
120. Alimov, A., et al., Loss of 14q31-q32.2 in renal cell carcinoma is associated with high malignancy grade and poor survival. Int J Oncol, 2004. 25(1): p. 179-85.
121. Singh, L.S., et al., Ovarian cancer G protein-coupled receptor 1, a new metastasis suppressor gene in prostate cancer. J Natl Cancer Inst, 2007. 99(17): p. 1313-27.
122. Markowski, J., et al., Metal-proteinase ADAM12, kinesin 14 and checkpoint suppressor 1 as new molecular markers of laryngeal carcinoma. Eur Arch Otorhinolaryngol, 2009. 266(10): p. 1501-7.
123. Staub, E., et al., A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer. Mol Cancer, 2006. 5: p. 37.
124. Parikh, R.A., et al., Loss of distal 11q is associated with DNA repair deficiency and reduced sensitivity to ionizing radiation in head and neck squamous cell carcinoma. Genes Chromosomes Cancer, 2007. 46(8): p. 761-75.
125. Cui, Y., et al., OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation. PLoS One, 2008. 3(8): p. e2990.
126. Viloria, C.G., et al., Genetic inactivation of ADAMTS15 metalloprotease in human colorectal cancer. Cancer Res, 2009. 69(11): p. 4926-34.
127. Allinen, M., et al., Analysis of 11q21-24 loss of heterozygosity candidate target genes in breast cancer: indications of TSLC1 promoter hypermethylation. Genes Chromosomes Cancer, 2002. 34(4): p. 384-9.
128. Ando, K., et al., Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation. Int J Cancer, 2008. 123(9): p. 2087-94.
129. Yeo, M., et al., Loss of SM22 is a characteristic signature of colon carcinogenesis and its restoration suppresses colon tumorigenicity in vivo and in vitro. Cancer, 2010. 116(11): p. 2581-9.
130. Gorringe, K.L., et al., High-resolution single nucleotide polymorphism array analysis of epithelial ovarian cancer reveals numerous microdeletions and amplifications. Clin Cancer Res, 2007. 13(16): p. 4731-9.
131. Chiang, D.Y., et al., Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Research, 2008. 68(16): p. 6779-6788.
132. Haverty, P.M., et al., High-resolution analysis of copy number alterations and associated expression changes in ovarian tumors. BMC Med Genomics, 2009. 2: p. 21.
133. Shuib, S., et al., Copy number profiling in von hippel-lindau disease renal cell carcinoma. Genes Chromosomes and Cancer, 2011. 50(7): p. 479-488.
134. Sun, M., et al., AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am J Pathol, 2001. 159(2): p. 431-7.
135. Regala, R.P., et al., Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer. Cancer Res, 2005. 65(19): p. 8905-11.
136. Imoto, I., et al., Identification of ZASC1 encoding a Kruppel-like zinc finger protein as a novel target for 3q26 amplification in esophageal squamous cell carcinomas. Cancer Res, 2003. 63(18): p. 5691-6.
137. Yokoi, S., et al., TERC identified as a probable target within the 3q26 amplicon that is detected frequently in non-small cell lung cancers. Clin Cancer Res, 2003. 9(13): p. 4705-13.
138. Nanjundan, M., et al., Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer. Cancer Res, 2007. 67(7): p. 3074-84.
139. Yang, Y.L., et al., Amplification of PRKCI, located in 3q26, is associated with lymph node metastasis in esophageal squamous cell carcinoma. Genes Chromosomes Cancer, 2008. 47(2): p. 127-36.
140. Yen, C.C., et al., Copy number changes of target genes in chromosome 3q25.3-qter of esophageal squamous cell carcinoma: TP63 is amplified in early carcinogenesis but down-regulated as disease progressed. World J Gastroenterol, 2005. 11(9): p. 1267-72.
141. Iyoda, M., et al., Epithelial cell transforming sequence 2 in human oral cancer. PLoS One, 2010. 5(11): p. e14082.
142. Hermsen, M., et al., New chromosomal regions with high-level amplifications in squamous cell carcinomas of the larynx and pharynx, identified by comparative genomic hybridization. J Pathol, 2001. 194(2): p. 177-82.
143. Sonoda, G., et al., Comparative genomic hybridization detects frequent overrepresentation of chromosomal material from 3q26, 8q24, and 20q13 in human ovarian carcinomas. Genes Chromosomes Cancer, 1997. 20(4): p. 320-8.
144. Petersen, I., et al., Patterns of chromosomal imbalances in adenocarcinoma and squamous cell carcinoma of the lung. Cancer Res, 1997. 57(12): p. 2331-5.
145. Nakakuki, K., et al., Novel targets for the 18p11.3 amplification frequently observed in esophageal squamous cell carcinomas. Carcinogenesis, 2002. 23(1): p. 19-24.
146. Silva, J.M., et al., Cyfip1 is a putative invasion suppressor in epithelial cancers. Cell, 2009. 137(6): p. 1047-61.
147. Takenawa, T. and S. Suetsugu, The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol, 2007. 8(1): p. 37-48.
148. Furuta, H., et al., NDRG2 is a candidate tumor-suppressor for oral squamous-cell carcinoma. Biochem Biophys Res Commun, 2010. 391(4): p. 1785-91.
149. Melotte, V., et al., The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications. FASEB J, 2010. 24(11): p. 4153-66.
150. Deng, Y., et al., N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation. Int J Cancer, 2003. 106(3): p. 342-7.
151. Tepel, M., et al., Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma. Int J Cancer, 2008. 123(9): p. 2080-6.
152. Lusis, E.A., et al., Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res, 2005. 65(16): p. 7121-6.
153. Lorentzen, A., et al., Expression of NDRG2 is down-regulated in high-risk adenomas and colorectal carcinoma. BMC Cancer, 2007. 7: p. 192.
154. Assamaki, R., et al., Array comparative genomic hybridization analysis of chromosomal imbalances and their target genes in gastrointestinal stromal tumors. Genes Chromosomes Cancer, 2007. 46(6): p. 564-76.
155. Choi, S.C., et al., Expression of NDRG2 is related to tumor progression and survival of gastric cancer patients through Fas-mediated cell death. Exp Mol Med, 2007. 39(6): p. 705-14.
156. Wang, L., et al., NDRG2 is a new HIF-1 target gene necessary for hypoxia-induced apoptosis in A549 cells. Cell Physiol Biochem, 2008. 21(1-3): p. 239-50.
157. Liu, J., et al., HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells. Exp Cell Res, 2010. 316(12): p. 1985-93.
158. Cheng, Y., et al., Monochromosome transfer provides functional evidence for growth-suppressive genes on chromosome 14 in nasopharyngeal carcinoma. Genes Chromosomes Cancer, 2003. 37(4): p. 359-68.
159. Ambatipudi, S., et al., Genomic profiling of advanced-stage oral cancers reveals chromosome 11q alterations as markers of poor clinical outcome. PLoS One, 2011. 6(2): p. e17250.
160. Vekony, H., et al., DNA copy number gains at loci of growth factors and their receptors in salivary gland adenoid cystic carcinoma. Clin Cancer Res, 2007. 13(11): p. 3133-9.
161. Warner, G.C., et al., Molecular classification of oral cancer by cDNA microarrays identifies overexpressed genes correlated with nodal metastasis. Int J Cancer, 2004. 110(6): p. 857-68.
162. Miwa, N., et al., Involvement of claudin-1 in the beta-catenin/Tcf signaling pathway and its frequent upregulation in human colorectal cancers. Oncol Res, 2001. 12(11-12): p. 469-76.
163. Chang, S.S. and J. Califano, Current status of biomarkers in head and neck cancer. J Surg Oncol, 2008. 97(8): p. 640-3.
164. Huang, S.F., et al., Relationship between epidermal growth factor receptor gene copy number and protein expression in oral cavity squamous cell carcinoma. Oral Oncol, 2011.
165. Matta, A., et al., Over-expression of 14-3-3zeta is an early event in oral cancer. BMC Cancer, 2007. 7: p. 169.
166. Chen, Y.J., et al., Genome-wide profiling of oral squamous cell carcinoma. J Pathol, 2004. 204(3): p. 326-32.
167. Liu, H.S., et al., Detection of copy number amplification of cyclin D1 (CCND1) and cortactin (CTTN) in oral carcinoma and oral brushed samples from areca chewers. Oral Oncol, 2009. 45(12): p. 1032-6.
168. Sugahara, K., et al., Combination effects of distinct cores in 11q13 amplification region on cervical lymph node metastasis of oral squamous cell carcinoma. Int J Oncol, 2011. 39(4): p. 761-9.
169. Xia, J., et al., Amplifications of TAOS1 and EMS1 genes in oral carcinogenesis: association with clinicopathological features. Oral Oncol, 2007. 43(5): p. 508-14.
170. Snijders, A.M., et al., Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma. Oncogene, 2005. 24(26): p. 4232-42.
171. Freier, K., et al., Recurrent coamplification of cytoskeleton-associated genes EMS1 and SHANK2 with CCND1 in oral squamous cell carcinoma. Genes Chromosomes Cancer, 2006. 45(2): p. 118-25.
172. Jarvinen, A.K., et al., High-resolution copy number and gene expression microarray analyses of head and neck squamous cell carcinoma cell lines of tongue and larynx. Genes Chromosomes Cancer, 2008. 47(6): p. 500-9.
173. Lerdrup, M., et al., Depletion of the AP-1 repressor JDP2 induces cell death similar to apoptosis. Biochim Biophys Acta, 2005. 1745(1): p. 29-37.
174. Yuanhong, X., et al., Downregulation of AP-1 repressor JDP2 is associated with tumor metastasis and poor prognosis in patients with pancreatic carcinoma. Int J Biol Markers, 2010. 25(3): p. 136-40.
175. Nakaya, K., et al., Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array. Oncogene, 2007. 26(36): p. 5300-8.
176. Nakamura, E., et al., Frequent silencing of a putative tumor suppressor gene melatonin receptor 1 A (MTNR1A) in oral squamous-cell carcinoma. Cancer Sci, 2008. 99(7): p. 1390-400.
177. Toomes, C., et al., The presence of multiple regions of homozygous deletion at the CSMD1 locus in oral squamous cell carcinoma question the role of CSMD1 in head and neck carcinogenesis. Genes Chromosomes Cancer, 2003. 37(2): p. 132-40.
178. Chiba, T., et al., Epigenetic loss of mucosa-associated lymphoid tissue 1 expression in patients with oral carcinomas. Cancer Res, 2009. 69(18): p. 7216-23.
179. Loro, L.L., A.C. Johannessen, and O.K. Vintermyr, Loss of BCL-2 in the progression of oral cancer is not attributable to mutations. J Clin Pathol, 2005. 58(11): p. 1157-62.
180. Yoshizawa, K., et al., Loss of maspin is a negative prognostic factor for invasion and metastasis in oral squamous cell carcinoma. J Oral Pathol Med, 2009. 38(6): p. 535-9.