(3.235.236.13) 您好!臺灣時間:2021/05/15 03:29
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

: 
twitterline
研究生:黃祥富
研究生(外文):Shiang Fu Huang
論文名稱:台灣地區口腔鱗狀上皮細胞癌經由EGFR/PIK3CA/AKT2與p16INK4A/p53/MDM2產生細胞週期擾動
論文名稱(外文):Perturbation of Cell Cycle through EGFR/PIK3CA/AKT2 and p16INK4A/p53/MDM2 in Taiwanese Oral Squamous Cell Carcinomas
指導教授:謝玲玲謝玲玲引用關係
指導教授(外文):L. L. Hsieh
學位類別:博士
校院名稱:長庚大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:128
中文關鍵詞:口腔鱗狀上皮細胞癌表皮生長因子受體PIK3CAAKT2p16INK4AMDM2
外文關鍵詞:Oral Squamous Cell CarcinomaEGFRPIK3CAAKT2p16INK4AMDM2
相關次數:
  • 被引用被引用:0
  • 點閱點閱:365
  • 評分評分:
  • 下載下載:73
  • 收藏至我的研究室書目清單書目收藏:0
EGFR訊息傳遞路徑與細胞週期相關基因在人類癌症發展過程中極具重要性,因此本論文分析參與EGFR訊息傳遞之EGFR、PIK3CA與AKT2基因,及p16INK4A與MDM2細胞週期相關基因在台灣地區男性口腔鱗狀上皮細胞癌之角色。EGFR蛋白過度表現與基因增幅之頻率分別為46.88%與31.25%;但EGFR基因之突變率並不高(0.58%)。EGFR蛋白過度表現與基因增幅具統計顯著相關;同時腫瘤EGFR蛋白過度表現之病患有顯著較差之無病存活率與全存活率 (p值分別為0.016與0.005)。PIK3CA基因之突變頻率為4.10%,且皆位於第20個表現序列。PIK3CA與AKT2基因增幅頻率分別為40.5%與15.4%。PIK3CA基因活化(包括基因誤義突變與基因增幅)與AKT2基因增幅皆與病患無病存活率(p值分別為 0.008與 0.004)及全存活率(p值分別為0.020與 0.007)負相關。病患之腫瘤屬PIK3CA基因活化與AKT2基因增幅者,其無病存活率(p < 0.0001)與全存活率(p = 0.0006)均最差。綜合言之,病患之腫瘤為EGFR/PIK3CA/AKT2基因變異者,其無病存活率及全存活率皆較差(p值分別為0.0084與p = 0.0151)。
p16INK4A基因啟動子甲基化、突變與同合子缺失之頻率分別為32.24%、 15.10%與17.96%。p16INK4A基因突變主要發生於第58 (CGATGA,15.91%)與80譯碼子(CGATGA,29.55%)。另外發現p16INK4A不活化與p53基因突變有關(p = 0.004)。在MDM2 SNP309方面,病患屬G對偶基因型者發病年齡較早,且腫瘤屬分化不良者較多(χ2: p = 0.010)。病患為GG基因型且其腫瘤之p53基因為突變型者,其腫瘤易有淋巴結莢膜外擴散之現象(χ2: p = 0.043);同時,不論早期或晚期之口腔癌患者,其無病存活率均較差(p值分別為 0.026與0.001)。
結論:本論文發現EGFR/PIK3CA/AKT2與細胞週期相關基因(如p16INK4A、MDM2)在台灣地區口腔鱗狀上皮癌致癌過程中扮演重要角色。同時,EGFR/PIK3CA/AKT2訊息路徑可能是未來台灣地區口腔癌治療之標靶。
The genes involved in EGFR signaling pathway and cell cycle are important in the development of human cancers. The roles of EGFR, PIK3CA and AKT2 gene engaged in the EGFR signaling pathway as well as p16INK4A and MDM2 gene associated with cell cycle control are examined in Taiwanese male oral squamous cell carcinoma (OSCC). Overexpression and amplification of EGFR was found in 46.88% and 31.25% of OSCCs analyzed, respectively. However, the frequency of mutation in EGFR kinase domain was low (0.58%). EGFR protein overexpression was significantly associated with EGFR amplification. Furthermore, EGFR protein overexpression was associated with a poor prognosis both in disease-free survival (DFS, p = 0.016) and overall survival (OS, p = 0.005). PIK3CA mutation was found in 4.10% of OSCCs analyzed and all the mutations were in exon 20. The PIK3CA and AKT2 gene was amplified in 40.5% and 15.4% of OSCC tumors, respectively. Activation of PIK3CA (including missense mutation and amplification) and amplification of AKT2 was adversely associated with DFS (p = 0.008 and p = 0.004, respectively) and OS (p = 0.020 and p = 0.007, respectively). Patients with both activated PIK3CA and amplified AKT2 had the worst prognosis in DFS and OS (p < 0.0001 and p = 0.0006, respectively). Taken together, OSCC patients with EGFR/PIK3CA/AKT2 gene aberrations were associated with poor DFS and OS (p = 0.0084 and p = 0.0151, respectively).
The frequency of p16INK4A promoter methylation, mutation, and deletion was 32.24%, 15.10% and 17.96%, respectively. High frequencies of nonsense mutations at codons 58 (CGATGA, 15.91%) and 80 (CGATGA, 29.55%) were observed. Further analysis indicated that p16INK4A inactivation was associated with p53 mutation (p = 0.004). In MDM2 SNP309, the G allele was associated with early age of onset and poor differentiation of OSCC tumors (χ2: p = 0.010). The frequency of lymph node extracapsular spread was increased in individuals having both the GG genotype and p53 mutation (χ2: p = 0.043). Furthermore, Patients with GG genotype and p53 mutations had poor DFS in both early stage (p = 0.026) and advanced stage OSCC (p = 0.001).
In conclusion, both EGFR/PIK3CA/AKT2 and cell cycle related genes (e.g. p16INK4A and MDM2) are important in the carcinogenesis of OSCCs in Taiwan. The findings from the present study further indicated that the EGFR/PIK3CA/AKT2 pathway could be the future therapeutic targets for OSCCs in Taiwan.
致 謝 vi
中文摘要 vii
英文摘要 ix
第一章 前言 1
口腔癌之流行病學特徵 4
第二章 研究目的 7
第三章 文獻探討 9
3.1. EGFR蛋白過度表現、基因突變與基因增幅 9
3.2. PIK3CA/AKT2基因變異與癌症 10
3.3. p16INK4A基因失活 11
3.4. MDM2 SNP309與p53基因突變之聯合效應 12
第四章 研究材料與方法 14
病患、檢體與臨床診斷 14
4.1. EGFR免疫組織化學染色分析與評分 14
4.2. EGFR FISH分析與量化 15
4.3. 聚合酶連鎖反應-單股構形多形性分析(PCR-SSCP) 16
4.4. DNA定序分析 17
4.5. 複合式PCR–DHPLC分析PIK3CA和AKT2基因增幅與p16INK4A基因缺失 18
4.6. p16INK4A啟動子甲基化(promoter methylation)分析 19
4.7. 基質輔助雷射脫附游離/飛行時間質譜(matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, MALDI-TOF mass spectrometry)分析MDM2 309單一核苷酸多形性 20
4.8. 資料分析 20
第五章 結果 22
5.1. EGFR蛋白過度表現、基因突變及基因增幅與臨床病理變項間的相關性 22
5.2. PIK3CA、AKT2基因變異與臨床病理變項間的相關性 23
5.3. p16INK4A基因失活與臨床病理變項間的相關性 24
5.4. MDM2 SNP309於口腔鱗狀上皮細胞癌之角色 26
第六章 討論 28
6.1. EGFR蛋白過度表現、基因突變與基因增幅 28
6.2. PIK3CA/AKT2基因變異 32
6.3. p16INK4A基因失活 34
6.4. MDM2 SNP309的效應 37
第七章 結論 40
附錄 65
表3-1:各種腫瘤PIK3CA與AKT2基因增幅的相關研究 65
表3-2:頭頸部鱗狀上皮細胞癌p16INK4A基因失活的相關研究 67
表4-1:483位口腔鱗狀上皮細胞癌患者的臨床特徵 70
表4-2:本論文EGFR、PIK3CA、AKT2、16INK4A及MDM2基因相關分析引子之DNA序列及PCR重鏈溫度 71
表5-1:口腔鱗狀上皮細胞癌EGFR蛋白過度表現與臨床病理變項之相關性 73
表5-2:口腔鱗狀上皮細胞癌EGFR基因突變者之臨床表徵 75
表5-3:口腔鱗狀上皮細胞癌EGFR基因套數與臨床病理變項的相關性 76
表5-4:EGFR蛋白表現與基因套數的相關性分析 78
表5-5:口腔癌腫瘤組織PIK3CA基因突變特徵 79
表5-6:口腔鱗狀上皮細胞癌PIK3CA基因突變/增幅及AKT2基因增幅與臨床病理變項的的相關性 80
表5-7:Cox迴歸多變項分析PIK3CA基因變異及AKT2基因增幅在無病存活率與全存活率之聯合效應 82
表5-8:口腔鱗狀上皮細胞癌p16INK4A基因變異分析 83
表5-9:口腔鱗狀上皮細胞癌p16INK4A基因失活機制分析 84
表5-10:台灣男性口腔鱗狀上皮細胞癌p16INK4A基因的突變特徵 85
表5-11:口腔鱗狀上皮細胞癌p16INK4A基因突變型式與抽菸、喝酒、嚼檳榔的相關性分析 88
表5-12:口腔癌病患MDM2 SNP 309基因型與一般對照族群抽菸、喝酒、嚼食檳榔史的相關性分析 89
表5-13:MDM2 SNP 309基因型與腫瘤分化、淋巴結轉移、LNECS、p53突變的相關性分析 90
表5-14:MDM2 SNP 309基因型及腫瘤 p53突變對腫瘤LNECS的聯合效應分析 91
表6-1:頭頸部鱗狀上皮細胞癌及細胞株EGFR基因突變的相關研究 92
表6-2:口腔鱗狀上皮細胞癌p16INK4A基因突變的相關研究 95
圖1-1:頸部淋巴結的分區 97
圖1-2:頸部淋巴結轉移的機率會隨著腫瘤位置越往後(從嘴唇到口腔到口咽腔及下咽腔)而逐步增加 98
圖2-1:頭頸部腫瘤基因變異累積模式 99
圖3-1:生長因子受體及其下游相關基因訊息路徑與生物功能之示意圖 100
圖4-1:口腔鱗狀上皮細胞癌表皮生長因子受體(EGFR)免疫組織化學染色代表圖 101
圖4-2:EGFR基因為雙套體(A)、多倍體(B)與基因增幅(C)之代表圖 102
圖4-3:以單股構形多形性(SSCP)分析口腔癌腫瘤組織p16INK4A基因突變之代表圖 103
圖4-4:腫瘤組織p16INK4A 基因第二表現序列區段有點突變之DNA定序分析代表圖 104
圖4-5:以複合式PCR–DHPLC分析腫瘤組織p16INK4A基因第二表現序列缺失之代表圖 105
圖4-6:口腔癌腫瘤組織p16INK4A啟動子甲基化電泳分析代表圖 106
圖5-1:口腔癌EGFR蛋白過度表現與無病存活率(A)及全存活率(B)之相關性分析 107
圖5-2:EGFR突變之DNA直接定序結果 109
圖5-3:口腔癌EGFR基因套數與無病存活率(A)及全存活率(B)之相關性分析 108
圖5-4:EGFR蛋白過度表現與EGFR基因擴增顯著相關 110
圖5-5:口腔癌PIK3CA基因變異與無病存活率(A)及全存活率(B)之相關性分析 111
圖5-6:口腔癌AKT2基因增幅與無病存活率(A)及全存活率(B)之相關性分析 112
圖5-7:口腔癌PIK3CA基因變異及AKT2基因增幅與無病存活率(A)與全存活率(B)之聯合效應分析 113
圖5-8:口腔鱗狀上皮細胞癌p16INK4A基因突變圖譜 114
圖5-9:口腔鱗狀上皮細胞癌無病存活率(DFS)分析。(A)腫瘤組織p53突變之單獨效應;MDM2 SNP 309及腫瘤組織p53突變對早期(B)及有淋巴結轉移(C)之口腔癌與無病存活率之聯合效應分析 105,106
圖7-1:口腔癌EGFR/PIK3CA/AKT2基因變異之無病存活率(A)與全存活率(B)之相關性分析 117
1. International Agency for Research on Cancer (IARC). Tobacco smoking. IARC Monographs on the evaluation of carcinogenic risks to humans. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.(38). 1986. Lyon, IARC. 1986.
2. Hecht,SS, Carmella,SG, Murphy,SE, Foiles,PG, Chung,FL. Carcinogen biomarkers related to smoking and upper aerodigestive tract cancer. J Cell Biochem.Suppl. 1993;17F:27-35.
3. Hoffmann,D, Adams,JD, Brunnemann,KD, Hecht,SS. Assessment of tobacco-specific N-nitrosamines in tobacco products. Cancer Res. 1979;39:2505-2509.
4. Idris,AM, Nair,J, Ohshima,H et al. Unusually high levels of carcinogenic tobacco-specific nitrosamines in Sudan snuff (toombak). Carcinogenesis. 1991;12:1115-1118.
5. Shah,JP, Johnson,NW, Batsakis,JG. Oral Cancer. London, U.K.: Martin Dunitz; 2003.
6. Hung,HC, Chuang,J, Chien,YC et al. Genetic polymorphisms of CYP2E1, GSTM1, and GSTT1; environmental factors and risk of oral cancer. Cancer Epidemiol.Biomarkers Prev. 1997;6:901-905.
7. Lafuente,A, Maristany,M, Arias,C et al. Glutathione and glutathione S-transferases in human squamous cell carcinomas of the larynx and GSTM1 dependent risk. Anticancer Res. 1998;18:107-111.
8. International Agency for Research on Cancer (IARC). Alcohol drinking. IARC Monographs on the evaluation of carcinogenic risks to humans. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.(44). 1988. Lyon, IARC. 1988.
9. Squier,CA, Cox,P, Hall,BK. Enhanced penetration of nitrosonornicotine across oral mucosa in the presence of ethanol. J Oral Pathol. 1986;15:276-279.
10. McCoy,GD, Wynder,EL. Etiological and preventive implications in alcohol carcinogenesis. Cancer Res. 1979;39:2844-2850.
11. Homann,N, Tillonen,J, Meurman,JH et al. Increased salivary acetaldehyde levels in heavy drinkers and smokers: a microbiological approach to oral cavity cancer. Carcinogenesis. 2000;21:663-668.
12. Homann,N, Tillonen,J, Rintamaki,H, Salaspuro,M, Lindqvist,C, Meurman,JH. Poor dental status increases acetaldehyde production from ethanol in saliva: a possible link to increased oral cancer risk among heavy drinkers. Oral Oncol. 2001;37:153-158.
13. Homann,N, Jousimies-Somer,H, Jokelainen,K, Heine,R, Salaspuro,M. High acetaldehyde levels in saliva after ethanol consumption: methodological aspects and pathogenetic implications. Carcinogenesis. 1997;18:1739-1743.
14. Kato,I, Nomura,AM. Alcohol in the aetiology of upper aerodigestive tract cancer. Eur.J Cancer B Oral Oncol. 1994;30B:75-81.
15. Harris,C, Warnakulasuriya,KA, Gelbier,S, Johnson,NW, Peters,TJ. Oral and dental health in alcohol misusing patients. Alcohol Clin Exp.Res. 1997;21:1707-1709.
16. International Agency for Research on Cancer (IARC). Betel-quid and areca-nut chewing and some areca-nut related nitrosamines. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.(85), 11-18. 2003. 2003.
17. Sundqvist,K, Liu,Y, Nair,J, Bartsch,H, Arvidson,K, Grafstrom,RC. Cytotoxic and genotoxic effects of areca nut-related compounds in cultured human buccal epithelial cells. Cancer Res. 1989;49:5294-5298.
18. Shirname,LP, Menon,MM, Nair,J, Bhide,SV. Correlation of mutagenicity and tumorigenicity of betel quid and its ingredients. Nutr.Cancer. 1983;5:87-91.
19. Stich,HF, Stich,W, Lam,PP. Potentiation of genotoxicity by concurrent application of compounds found in betel quid: arecoline, eugenol, quercetin, chlorogenic acid and Mn2+. Mutat.Res. 1981;90:355-363.
20. Panigrahi,GB, Rao,AR. Chromosome-breaking ability of arecoline, a major betel-nut alkaloid, in mouse bone-marrow cells in vivo. Mutat.Res. 1982;103:197-204.
21. Ko,YC, Huang,YL, Lee,CH, Chen,MJ, Lin,LM, Tsai,CC. Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med. 1995;24:450-453.
22. Wen,CP, Tsai,SP, Cheng,TY et al. Uncovering the relation between betel quid chewing and cigarette smoking in Taiwan. Tob.Control. 2005;14 Suppl 1:i16-i22.
23. Yeudall,WA. Human papillomaviruses and oral neoplasia. Eur.J Cancer B Oral Oncol. 1992;28B:61-66.
24. Woods,KV, Shillitoe,EJ, Spitz,MR, Schantz,SP, Adler-Storthz,K. Analysis of human papillomavirus DNA in oral squamous cell carcinomas. J Oral Pathol.Med. 1993;22:101-108.
25. Mao,EJ. Prevalence of human papillomavirus 16 and nucleolar organizer region counts in oral exfoliated cells from normal and malignant epithelia. Oral Surg.Oral Med.Oral Pathol.Oral Radiol.Endod. 1995;80:320-329.
26. Snijders,PJ, van den Brule,AJ, Meijer,CJ, Walboomers,JM. Papillomaviruses and cancer of the upper digestive and respiratory tracts. Curr.Top.Microbiol.Immunol. 1994;186:177-198.
27. Giovannelli,L, Campisi,G, Lama,A et al. Human papillomavirus DNA in oral mucosal lesions. J Infect.Dis. 2002;185:833-836.
28. Miller,CS, Johnstone,BM. Human papillomavirus as a risk factor for oral squamous cell carcinoma: a meta-analysis, 1982-1997. Oral Surg.Oral Med.Oral Pathol.Oral Radiol.Endod. 2001;91:622-635.
29. Taiwan cancer registry, 2006 annual report. http://crs.cph.ntu.edu.tw/ . 1-1-2006.
30. Fleming,ID, Cooper,JS, Henson,DE, et al. AJCC Cancer Staging Manual. 5th edition ed. Philadelphia: Lippincott Williams & Wilkins; 1997.
31. Lindberg,R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer. 1972;29:1446-1449.
32. Shah,JP. Cervical lymph node metastases--diagnostic, therapeutic, and prognostic implications. Oncology (Williston.Park). 1990;4:61-69.
33. Shah,JP, Candela,FC, Poddar,AK. The patterns of cervical lymph node metastases from squamous carcinoma of the oral cavity. Cancer. 1990;66:109-113.
34. Shah,JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am.J Surg. 1990;160:405-409.
35. Shah,JP, Medina,JE, Shaha,AR, Schantz,SP, Marti,JR. Cervical lymph node metastasis. Curr.Probl.Surg. 1993;30:1-335.
36. Byers,RM, Weber,RS, Andrews,T, McGill,D, Kare,R, Wolf,P. Frequency and therapeutic implications of "skip metastases" in the neck from squamous carcinoma of the oral tongue. Head Neck. 1997;19:14-19.
37. Liao,CT, Wang,HM, Ng,SH et al. Good tumor control and survivals of squamous cell carcinoma of buccal mucosa treated with radical surgery with or without neck dissection in Taiwan. Oral Oncol. 2006;42:800-809.
38. Ballantyne,AJ. Significance of retropharyngeal nodes in cancer of the head and neck. Am.J Surg. 1964;108:500-504.
39. Houck,JR, Medina,JE. Management of cervical lymph nodes in squamous carcinomas of the head and neck. Semin.Surg.Oncol. 1995;11:228-239.
40. Leemans,CR, Tiwari,R, Nauta,JJ, van,dW, I, Snow,GB. Regional lymph node involvement and its significance in the development of distant metastases in head and neck carcinoma. Cancer. 1993;71:452-456.
41. Tytor,M, Olofsson,J. Prognostic factors in oral cavity carcinomas. Acta Otolaryngol Suppl. 1992;492:75-78.
42. Kalnins,IK, Leonard,AG, Sako,K, Razack,MS, Shedd,DP. Correlation between prognosis and degree of lymph node involvement in carcinoma of the oral cavity. Am.J Surg. 1977;134:450-454.
43. Snow,GB, Patel,P, Leemans,CR, Tiwari,R. Management of cervical lymph nodes in patients with head and neck cancer. Eur.Arch.Otorhinolaryngol. 1992;249:187-194.
44. Spiro,RH. The management of neck nodes in head and neck cancer: a surgeon's view. Bull.N.Y.Acad.Med. 1985;61:629-637.
45. Grandi,C, Alloisio,M, Moglia,D et al. Prognostic significance of lymphatic spread in head and neck carcinomas: therapeutic implications. Head Neck Surg. 1985;8:67-73.
46. Johnson,JT, Myers,EN, Bedetti,CD, Barnes,EL, Schramm,VL, Jr., Thearle,PB. Cervical lymph node metastases. Incidence and implications of extracapsular carcinoma. Arch.Otolaryngol. 1985;111:534-537.
47. Leemans,CR, Tiwari,R, Nauta,JJ, van,dW, I, Snow,GB. Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor. Cancer. 1994;73:187-190.
48. Zelefsky,MJ, Harrison,LB, Fass,DE et al. Postoperative radiotherapy for oral cavity cancers: impact of anatomic subsite on treatment outcome. Head Neck. 1990;12:470-475.
49. Alvi,A, Johnson,JT. Extracapsular spread in the clinically negative neck (N0): implications and outcome. Otolaryngol Head Neck Surg. 1996;114:65-70.
50. Andersen,PE, Cambronero,E, Shaha,AR, Shah,JP. The extent of neck disease after regional failure during observation of the N0 neck. Am.J Surg. 1996;172:689-691.
51. Carter,RL, Barr,LC, O'Brien,CJ, Soo,KC, Shaw,HJ. Transcapsular spread of metastatic squamous cell carcinoma from cervical lymph nodes. Am J Surg. 1985;150:495-499.
52. Shah,JP, Cendon,RA, Farr,HW, Strong,EW. Carcinoma of the oral cavity. factors affecting treatment failure at the primary site and neck. Am.J Surg. 1976;132:504-507.
53. Silver,CE, Moisa,II. Elective treatment of the neck in cancer of the oral tongue. Semin.Surg.Oncol. 1991;7:14-19.
54. Soo,KC, Tan,EH, Wee,J et al. Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison. Br.J Cancer. 2005;93:279-286.
55. Amdur,RJ, Parsons,JT, Mendenhall,WM, Million,RR, Stringer,SP, Cassisi,NJ. Postoperative irradiation for squamous cell carcinoma of the head and neck: an analysis of treatment results and complications. Int.J Radiat.Oncol Biol.Phys. 1989;16:25-36.
56. Ampil,F, Datta,R, Shockley,W. Adjuvant postoperative external beam radiotherapy in head and neck cancer. J Oral Maxillofac.Surg. 1988;46:569-573.
57. Cooper,JS, Pajak,TF, Forastiere,AA et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N.Engl.J Med. 2004;350:1937-1944.
58. Cooper,JS. Postoperative irradiation in head and neck cancer. Int.J Radiat.Oncol Biol.Phys. 1993;26:181-182.
59. Bernier,J, Domenge,C, Ozsahin,M et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N.Engl.J Med. 2004;350:1945-1952.
60. Bernier,J, Cooper,JS, Pajak,TF et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005;27:843-850.
61. Bernier,J, Cooper,JS. Chemoradiation after surgery for high-risk head and neck cancer patients: how strong is the evidence? Oncologist. 2005;10:215-224.
62. Martin,H, del Valle,B, Ehrlich,H, Cahan,WG. Neck dissection. Cancer. 1951;4:441-499.
63. Maddox,WA, Sherlock,EC, Evans,WB. Cancer of the tongue: review of thirteen-year experience--1955-1968. Am.Surg. 1971;37:624-650.
64. Schleuning,AJ, Summers,GW. Carcinoma of the tongue: review of 220 cases. Laryngoscope. 1972;82:1446-1454.
65. Spiro,RH, Alfonso,AE, Farr,HW, Strong,EW. Cervical node metastasis from epidermoid carcinoma of the oral cavity and oropharynx. A critical assessment of current staging. Am.J Surg. 1974;128:562-567.
66. Whitehurst,JO, Droulias,CA. Surgical treatment of squamous cell carcinoma of the oral tongue: factors influencing survival. Arch.Otolaryngol. 1977;103:212-215.
67. Shah,JP, Strong,E, Spiro,RH, Vikram,B. Surgical grand rounds. Neck dissection: current status and future possibilities. Clin Bull. 1981;11:25-33.
68. Snow,GB, Annyas,AA, van Slooten,EA, Bartelink,H, Hart,AA. Prognostic factors of neck node metastasis. Clin Otolaryngol.Allied Sci. 1982;7:185-192.
69. Vikram,B, Strong,EW, Shah,JP, Spiro,R. Failure in the neck following multimodality treatment for advanced head and neck cancer. Head Neck Surg. 1984;6:724-729.
70. Ho,CM, Lam,KH, Wei,WI, Lau,WF. Treatment of neck nodes in oral cancer. Surg.Oncol. 1992;1:73-78.
71. Snow,GB, van den Brekel,MW, Leemans,CR, Patel,P. Surgical management of cervical lymph nodes in patients with oral and oropharyngeal cancer. Recent Results Cancer Res. 1994;134:43-55.
72. Lore,JM, Jr. Early diagnosis and treatment of head and neck cancer. CA Cancer J Clin. 1995;45:325-327.
73. Supriatno, Harada,K, Hoque,MO, Bando,T, Yoshida,H, Sato,M. Overexpression of p27(Kip1) induces growth arrest and apoptosis in an oral cancer cell line. Oral Oncol. 2002;38:730-736.
74. Hsieh,LL, Wang,PF, Chen,IH et al. Characteristics of mutations in the p53 gene in oral squamous cell carcinoma associated with betel quid chewing and cigarette smoking in Taiwanese. Carcinogenesis. 2001;22:1497-1503.
75. Lin,SC, Chang,KW, Chang,CS et al. Alterations of p16/MTS1 gene in oral squamous cell carcinomas from Taiwanese. J Oral Pathol Med. 2000;29:159-166.
76. Paez,JG, Janne,PA, Lee,JC et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497-1500.
77. Pao,W, Miller,V, Zakowski,M et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc.Natl.Acad Sci.U.S.A. 2004;101:13306-13311.
78. Druker,BJ, Talpaz,M, Resta,DJ et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N.Engl J Med. 2001;344:1031-1037.
79. Demetri,GD, von Mehren,M, Blanke,CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N.Engl J Med. 2002;347:472-480.
80. Slamon,DJ, Leyland-Jones,B, Shak,S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N.Engl J Med. 2001;344:783-792.
81. Wakeling,AE, Guy,SP, Woodburn,JR et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 2002;62:5749-5754.
82. Ciardiello,F, Caputo,R, Bianco,R et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res. 2000;6:2053-2063.
83. Williams,KJ, Telfer,BA, Stratford,IJ, Wedge,SR. ZD1839 ('Iressa'), a specific oral epidermal growth factor receptor-tyrosine kinase inhibitor, potentiates radiotherapy in a human colorectal cancer xenograft model. Br.J Cancer. 2002;86:1157-1161.
84. Fukuoka,M, Yano,S, Giaccone,G et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 2003;21:2237-2246.
85. Kris,MG, Natale,RB, Herbst,RS et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290:2149-2158.
86. Huang,SF, Liu,HP, Li,LH et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res. 2004;10:8195-8203.
87. Rubin,GJ, Melhem,MF, Barnes,EL, Tweardy,DJ. Quantitative immunohistochemical analysis of transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer. 1996;78:1284-1292.
88. Chen,IH, Chang,JT, Liao,CT, Wang,HM, Hsieh,LL, Cheng,AJ. Prognostic significance of EGFR and Her-2 in oral cavity cancer in betel quid prevalent area cancer prognosis. Br.J Cancer. 2003;89:681-686.
89. Rosell,R, Taron,M, Reguart,N, Isla,D, Moran,T. Epidermal growth factor receptor activation: how exon 19 and 21 mutations changed our understanding of the pathway. Clin.Cancer Res. 2006;12:7222-7231.
90. Takehana,T, Kunitomo,K, Suzuki,S et al. Expression of epidermal growth factor receptor in gastric carcinomas. Clin Gastroenterol.Hepatol. 2003;1:438-445.
91. Ooi,A, Takehana,T, Li,X et al. Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study. Mod.Pathol. 2004;17:895-904.
92. Suzuki,S, Dobashi,Y, Sakurai,H, Nishikawa,K, Hanawa,M, Ooi,A. Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas. An immunohistochemical and fluorescence in situ hybridization study. Cancer. 2005;103:1265-1273.
93. Nakazawa,K, Dobashi,Y, Suzuki,S, Fujii,H, Takeda,Y, Ooi,A. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol. 2005;206:356-365.
94. Dobashi,Y, Takei,N, Suzuki,S, Yoneyama,H, Hanawa,M, Ooi,A. Aberration of epidermal growth factor receptor expression in bone and soft-tissue tumors: protein overexpression, gene amplification and activation of downstream molecules. Mod.Pathol. 2004;17:1497-1505.
95. Mrhalova,M, Plzak,J, Betka,J, Kodet,R. Epidermal growth factor receptor--its expression and copy numbers of EGFR gene in patients with head and neck squamous cell carcinomas. Neoplasma. 2005;52:338-343.
96. Chung,CH, Ely,K, McGavran,L et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin.Oncol. 2006;24:4170-4176.
97. Morrison,LE, Jacobson,KK, Friedman,M, Schroeder,JW, Coon,JS. Aberrant EGFR and chromosome 7 associate with outcome in laryngeal cancer. Laryngoscope. 2005;115:1212-1218.
98. Dancey,JE. Molecular targeting: PI3 kinase pathway. Ann.Oncol. 2004;15 Suppl 4:iv233-iv239.
99. Vogelstein,B, Kinzler,KW. Cancer genes and the pathways they control. Nat.Med. 2004;10:789-799.
100. Stokoe,D. The phosphoinositide 3-kinase pathway and cancer. Expert.Rev.Mol.Med. 2005;7:1-22.
101. Samuels,Y, Wang,Z, Bardelli,A et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.
102. Angulo,B, Suarez-Gauthier,A, Lopez-Rios,F et al. Expression signatures in lung cancer reveal a profile for EGFR-mutant tumours and identify selective PIK3CA overexpression by gene amplification. J Pathol. 2008;214:347-356.
103. Hashimoto,Y, Oga,A, Kawauchi,S et al. Amplification of 3q26 approximately qter correlates with tumor progression in head and neck squamous cell carcinomas. Cancer Genet.Cytogenet. 2001;129:52-56.
104. Bellacosa,A, de Feo,D, Godwin,AK et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int.J Cancer. 1995;64:280-285.
105. Cheng,JQ, Ruggeri,B, Klein,WM et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc.Natl.Acad Sci.U.S.A. 1996;93:3636-3641.
106. Pedrero,JM, Carracedo,DG, Pinto,CM et al. Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int.J Cancer. 2005;114:242-248.
107. Redon,R, Muller,D, Caulee,K, Wanherdrick,K, Abecassis,J, du,MS. A simple specific pattern of chromosomal aberrations at early stages of head and neck squamous cell carcinomas: PIK3CA but not p63 gene as a likely target of 3q26-qter gains. Cancer Res. 2001;61:4122-4129.
108. Woenckhaus,J, Steger,K, Werner,E et al. Genomic gain of PIK3CA and increased expression of p110alpha are associated with progression of dysplasia into invasive squamous cell carcinoma. J Pathol. 2002;198:335-342.
109. Lin,M, Smith,LT, Smiraglia,DJ et al. DNA copy number gains in head and neck squamous cell carcinoma. Oncogene. 2006;25:1424-1433.
110. Qiu,W, Schonleben,F, Li,X et al. PIK3CA mutations in head and neck squamous cell carcinoma. Clin.Cancer Res. 2006;12:1441-1446.
111. Lane,DP. Cancer. p53, guardian of the genome. Nature. 1992;358:15-16.
112. Lewin,B. Gene VIII. 2007.Prentice Hall, New Jersey, USA.
113. Sharpless,NE, Alson,S, Chan,S, Silver,DP, Castrillon,DH, DePinho,RA. p16(INK4a) and p53 deficiency cooperate in tumorigenesis. Cancer Res. 2002;62:2761-2765.
114. Reed,AL, Califano,J, Cairns,P et al. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res. 1996;56:3630-3633.
115. Kamb,A, Gruis,NA, Weaver-Feldhaus,J et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994;264:436-440.
116. Hasegawa,M, Nelson,HH, Peters,E, Ringstrom,E, Posner,M, Kelsey,KT. Patterns of gene promoter methylation in squamous cell cancer of the head and neck. Oncogene. 2002;21:4231-4236.
117. Tsai,CH, Yang,CC, Chou,LS, Chou,MY. The correlation between alteration of p16 gene and clinical status in oral squamous cell carcinoma. J Oral Pathol Med. 2001;30:527-531.
118. Sanchez-Cespedes,M, Esteller,M, Wu,L et al. Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res. 2000;60:892-895.
119. Shintani,S, Nakahara,Y, Mihara,M, Ueyama,Y, Matsumura,T. Inactivation of the p14(ARF), p15(INK4B) and p16(INK4A) genes is a frequent event in human oral squamous cell carcinomas. Oral Oncol. 2001;37:498-504.
120. Heinzel,PA, Balaram,P, Bernard,HU. Mutations and polymorphisms in the p53, p21 and p16 genes in oral carcinomas of Indian betel quid chewers. Int.J Cancer. 1996;68:420-423.
121. Kannan,K, Munirajan,AK, Krishnamurthy,J et al. The p16INK4alpha/p19ARF gene mutations are infrequent and are mutually exclusive to p53 mutations in Indian oral squamous cell carcinomas. Int.J Oncol. 2000;16:585-590.
122. Nakahara,Y, Shintani,S, Mihara,M, Kiyota,A, Ueyama,Y, Matsumura,T. Alterations of Rb, p16(INK4A) and cyclin D1 in the tumorigenesis of oral squamous cell carcinomas. Cancer Lett. 2000;160:3-8.
123. Sartor,M, Steingrimsdottir,H, Elamin,F et al. Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines. Br.J Cancer. 1999;80:79-86.
124. González,MV, Pello,MF, Lopéz-Larrea,C, Suärez,C, Menëndez,MJ, Coto,E. Deletion and methylation of the tumour suppressor gene p16/CDKN2 in primary head and neck squamous cell carcinoma. J Clin.Pathol. 1997;50:509-512.
125. Zhao,Y, Zhang,S, Fu,B, Xiao,C. Abnormalities of tumor suppressor genes P16 and P15 in primary maxillofacial squamous cell carcinomas. Cancer Genet.Cytogenet. 1999;112:26-33.
126. Huang,MJ, Yeh,KT, Shih,HC et al. The correlation between CpG methylation and protein expression of P16 in oral squamous cell carcinomas. Int.J Mol.Med. 2002;10:551-554.
127. Hollstein,M, Sidransky,D, Vogelstein,B, Harris,CC. p53 mutations in human cancers. Science. 1991;253:49-53.
128. Levine,AJ, Momand,J, Finlay,CA. The p53 tumour suppressor gene. Nature. 1991;351:453-456.
129. Polyak,K, Xia,Y, Zweier,JL, Kinzler,KW, Vogelstein,B. A model for p53-induced apoptosis. Nature. 1997;389:300-305.
130. Vogelstein,B, Lane,D, Levine,AJ. Surfing the p53 network. Nature. 2000;408:307-310.
131. Zhao,R, Gish,K, Murphy,M et al. Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev. 2000;14:981-993.
132. Mirza,A, Wu,Q, Wang,L et al. Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression. Oncogene. 2003;22:3645-3654.
133. Ko,LJ, Prives,C. p53: puzzle and paradigm. Genes Dev. 1996;10:1054-1072.
134. Royds,JA, Iacopetta,B. p53 and disease: when the guardian angel fails. Cell Death.Differ. 2006;13:1017-1026.
135. Bond,GL, Hu,W, Bond,EE et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119:591-602.
136. Menin,C, Scaini,MC, De Salvo,GL et al. Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status. J Natl.Cancer Inst. 2006;98:285-288.
137. Boersma,BJ, Howe,TM, Goodman,JE et al. Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl.Cancer Inst. 2006;98:911-919.
138. Bond,GL, Hirshfield,KM, Kirchhoff,T et al. MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res. 2006;66:5104-5110.
139. Ko,YC, Huang,YL, Lee,CH, Chen,MJ, Lin,LM, Tsai,CC. Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med. 1995;24:450-453.
140. Duke,JA. Handbook of phytochemical constituents of GRAS herbs and other economic plants. Boca Raton, FL. CRC Press.; 1992.
141. Nunez-de la Mora,A, Chatterton,RT, Mateo,ET, Jesmin,F, Bentley,GR. Effect of chewing betel nut on measurements of salivary progesterone and estradiol. Am.J Phys.Anthropol. 2007;132:311-315.
142. Association of Directors of Anatomic and Surgical Pathology. Recommendations for the reporting of specimens containing oral cavity and oropharynx neoplasms. Mod.Pathol. 2000;13:1038-1041.
143. Wu,CM, Tang,R, Chen,JR et al. Humoral response to p53 is associated with conserved domains II and IV mutations in human colorectal cancer: a case-control study in Taiwan. Oncol Rep. 2004;12:1045-1051.
144. Lo,HW, Xia,W, Wei,Y, Ali-Seyed,M, Huang,SF, Hung,MC. Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. Cancer Res. 2005;65:338-348.
145. Hirsch,FR, Varella-Garcia,M, McCoy,J 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;23:6838-6845.
146. Cappuzzo,F, Hirsch,FR, Rossi,E et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl.Cancer Inst. 2005;97:643-655.
147. Tohma,Y, Gratas,C, Biernat,W et al. PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol.Exp.Neurol. 1998;57:684-689.
148. Herman,JG, Graff,JR, Myohanen,S, Nelkin,BD, Baylin,SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc.Natl.Acad Sci.U.S.A. 1996;93:9821-9826.
149. Liao,HK, Su,YN, Kao,HY, Hung,CC, Wang,HT, Chen,YJ. Parallel minisequencing followed by multiplex matrix-assisted laser desorption/ionization mass spectrometry assay for beta-thalassemia mutations. J Hum.Genet. 2005;50:139-150.
150. Stanssens,P, Zabeau,M, Meersseman,G et al. High-throughput MALDI-TOF discovery of genomic sequence polymorphisms. Genome Res. 2004;14:126-133.
151. Vivanco,I, Sawyers,CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat.Rev.Cancer. 2002;2:489-501.
152. Seethala,RR, Gooding,WE, Handler,PN et al. Immunohistochemical analysis of phosphotyrosine signal transducer and activator of transcription 3 and epidermal growth factor receptor autocrine signaling pathways in head and neck cancers and metastatic lymph nodes. Clin Cancer Res. 2008;14:1303-1309.
153. Pao,W, Miller,VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin.Oncol. 2005;23:2556-2568.
154. Cohen,EE, Rosen,F, Stadler,WM et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin.Oncol. 2003;21:1980-1987.
155. Lynch,TJ, Bell,DW, Sordella,R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N.Engl J Med. 2004;350:2129-2139.
156. Cohen,EE, Lingen,MW, Martin,LE et al. Response of some head and neck cancers to epidermal growth factor receptor tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR. Clin.Cancer Res. 2005;11:8105-8108.
157. Loeffler-Ragg,J, Witsch-Baumgartner,M, Tzankov,A et al. Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. Eur.J Cancer. 2006;42:109-111.
158. Lemos-Gonzalez,Y, Paez,dlC, Rodriguez-Berrocal,FJ, Rodriguez-Pineiro,AM, Pallas,E, Valverde,D. Absence of Activating Mutations in the EGFR Kinase Domain in Spanish Head and Neck Cancer Patients. Tumour.Biol. 2007;28:273-279.
159. Lee,JW, Soung,YH, Kim,SY et al. Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2005;11:2879-2882.
160. Na,II, Kang,HJ, Cho,SY et al. EGFR mutations and human papillomavirus in squamous cell carcinoma of tongue and tonsil. Eur.J Cancer. 2007;43:520-526.
161. Lee,JW, Soung,YH, Kim,SY et al. Absence of EGFR mutation in the kinase domain in common human cancers besides non-small cell lung cancer. Int.J Cancer. 2005;113:510-511.
162. Riely,GJ, Pao,W, Pham,D et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin.Cancer Res. 2006;12:839-844.
163. Shigematsu,H, Lin,L, Takahashi,T et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl.Cancer Inst. 2005;97:339-346.
164. Toyooka,S, Matsuo,K, Shigematsu,H et al. The impact of sex and smoking status on the mutational spectrum of epidermal growth factor receptor gene in non small cell lung cancer. Clin.Cancer Res. 2007;13:5763-5768.
165. Paz-Ares,L, Douillard,JY, Koralewski,P et al. Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer. J Clin.Oncol. 2006;24:1428-1434.
166. Saltz,LB, Meropol,NJ, Loehrer,PJ, Sr., Needle,MN, Kopit,J, Mayer,RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201-1208.
167. Mignatti,P, Rifkin,DB. Nonenzymatic interactions between proteinases and the cell surface: novel roles in normal and malignant cell physiology. Adv.Cancer Res. 2000;78:103-157.
168. Riedel,F, Gotte,K, Schwalb,J, Bergler,W, Hormann,K. Expression of 92-kDa type IV collagenase correlates with angiogenic markers and poor survival in head and neck squamous cell carcinoma. Int.J Oncol. 2000;17:1099-1105.
169. Arkonac,BM, Foster,LC, Sibinga,NE et al. Vascular endothelial growth factor induces heparin-binding epidermal growth factor-like growth factor in vascular endothelial cells. J Biol.Chem. 1998;273:4400-4405.
170. Pepper,MS, Mandriota,SJ, Jeltsch,M, Kumar,V, Alitalo,K. Vascular endothelial growth factor (VEGF)-C synergizes with basic fibroblast growth factor and VEGF in the induction of angiogenesis in vitro and alters endothelial cell extracellular proteolytic activity. J Cell Physiol. 1998;177:439-452.
171. Thomas,GT, Lewis,MP, Speight,PM. Matrix metalloproteinases and oral cancer. Oral Oncol. 1999;35:227-233.
172. Kusukawa,J, Harada,H, Shima,I, Sasaguri,Y, Kameyama,T, Morimatsu,M. The significance of epidermal growth factor receptor and matrix metalloproteinase-3 in squamous cell carcinoma of the oral cavity. Eur.J Cancer B Oral Oncol. 1996;32B:217-221.
173. charoenrat,P, Rhys-Evans,PH, Archer,DJ, Eccles,SA. C-erbB receptors in squamous cell carcinomas of the head and neck: clinical significance and correlation with matrix metalloproteinases and vascular endothelial growth factors. Oral Oncol. 2002;38:73-80.
174. Ellerbroek,SM, Halbleib,JM, Benavidez,M et al. Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association. Cancer Res. 2001;61:1855-1861.
175. Bonner,JA, Harari,PM, Giralt,J et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N.Engl.J Med. 2006;354:567-578.
176. Italiano,A, Follana,P, Caroli,FX et al. Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number. Ann.Surg.Oncol. 2008;15:649-654.
177. Cappuzzo,F, Finocchiaro,G, Rossi,E et al. EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann.Oncol. 2008;19:717-723.
178. Tanaka,Y, Kanai,F, Tada,M et al. Absence of PIK3CA hotspot mutations in hepatocellular carcinoma in Japanese patients. Oncogene. 2006;25:2950-2952.
179. Kozaki,K, Imoto,I, Pimkhaokham,A et al. PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma. Cancer Sci. 2006;97:1351-1358.
180. Ikenoue,T, Kanai,F, Hikiba,Y et al. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res. 2005;65:4562-4567.
181. Isakoff,SJ, Engelman,JA, Irie,HY et al. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005;65:10992-11000.
182. Kang,S, Bader,AG, Vogt,PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc.Natl.Acad.Sci.U.S.A. 2005;102:802-807.
183. Samuels,Y, Diaz,LA, Jr., Schmidt-Kittler,O et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell. 2005;7:561-573.
184. Shayesteh,L, Lu,Y, Kuo,WL et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat.Genet. 1999;21:99-102.
185. Yamamoto,H, Shigematsu,H, Nomura,M et al. PIK3CA Mutations and Copy Number Gains in Human Lung Cancers. Cancer Res. 2008;68:6913-6921.
186. Kawano,O, Sasaki,H, Okuda,K et al. PIK3CA gene amplification in Japanese non-small cell lung cancer. Lung Cancer. 2007;58:159-160.
187. Estilo,CL, Charoenrat,P, Ngai,I et al. The role of novel oncogenes squamous cell carcinoma-related oncogene and phosphatidylinositol 3-kinase p110alpha in squamous cell carcinoma of the oral tongue. Clin.Cancer Res. 2003;9:2300-2306.
188. Raynaud,FI, Eccles,S, Clarke,PA et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res. 2007;67:5840-5850.
189. Lim,J, Kim,JH, Paeng,JY et al. Prognostic value of activated Akt expression in oral squamous cell carcinoma. J Clin.Pathol. 2005;58:1199-1205.
190. Tang,JM, He,QY, Guo,RX, Chang,XJ. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer. 2006;51:181-191.
191. Larue,L, Bellacosa,A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene. 2005;24:7443-7454.
192. Hagemann,T, Bozanovic,T, Hooper,S et al. Molecular profiling of cervical cancer progression. Br.J Cancer. 2007;96:321-328.
193. Shao,J, Sheng,H, Inoue,H, Morrow,JD, DuBois,RN. Regulation of constitutive cyclooxygenase-2 expression in colon carcinoma cells. J Biol.Chem. 2000;275:33951-33956.
194. Sheng,H, Shao,J, Washington,MK, DuBois,RN. Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J Biol.Chem. 2001;276:18075-18081.
195. El Deiry,WS. Akt takes centre stage in cell-cycle deregulation. Nat.Cell Biol. 2001;3:E71-E73.
196. Kureishi,Y, Luo,Z, Shiojima,I et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat.Med. 2000;6:1004-1010.
197. Hsu,AL, Ching,TT, Wang,DS, Song,X, Rangnekar,VM, Chen,CS. The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J Biol.Chem. 2000;275:11397-11403.
198. Page,C, Lin,HJ, Jin,Y et al. Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis. Anticancer Res. 2000;20:407-416.
199. Hu,L, Zaloudek,C, Mills,GB, Gray,J, Jaffe,RB. In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin.Cancer Res. 2000;6:880-886.
200. Rocco,JW, Sidransky,D. p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp.Cell Res. 2001;264:42-55.
201. Kresty,LA, Mallery,SR, Knobloch,TJ et al. Alterations of p16(INK4a) and p14(ARF) in patients with severe oral epithelial dysplasia. Cancer Res. 2002;62:5295-5300.
202. van der Riet,P, Nawroz,H, Hruban,RH et al. Frequent loss of chromosome 9p21-22 early in head and neck cancer progression. Cancer Res. 1994;54:1156-1158.
203. Yanagawa,N, Tamura,G, Oizumi,H, Takahashi,N, Shimazaki,Y, Motoyama,T. Frequent epigenetic silencing of the p16 gene in non-small cell lung cancers of tobacco smokers. Jpn J Cancer Res. 2002;93:1107-1113.
204. Poi,MJ, Yen,T, Li,J et al. Somatic INK4a-ARF locus mutations: a significant mechanism of gene inactivation in squamous cell carcinomas of the head and neck. Mol.Carcinog. 2001;30:26-36.
205. Ruas,M, Peters,G. The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim.Biophys.Acta. 1998;1378:F115-F177.
206. Thongsuksai,P, Boonyaphiphat,P, Sriplung,H, Sudhikaran,W. p53 mutations in betel-associated oral cancer from Thailand. Cancer Lett. 2003;201:1-7.
207. Chen,CL, Chi,CW, Chang,KW, Liu,TY. Safrole-like DNA adducts in oral tissue from oral cancer patients with a betel quid chewing history. Carcinogenesis. 1999;20:2331-2334.
208. Ingle,CA, Drinkwater,NR. Mutational specificities of 1'-acetoxysafrole, N-benzoyloxy-N-methyl-4-aminoazobenzene, and ethyl methanesulfonate in human cells. Mutat.Res. 1989;220:133-142.
209. Prokopczyk,B, Rivenson,A, Bertinato,P, Brunnemann,KD, Hoffmann,D. 3-(Methylnitrosamino)propionitrile: occurrence in saliva of betel quid chewers, carcinogenicity, and DNA methylation in F344 rats. Cancer Res. 1987;47:467-471.
210. Horsfall,MJ, Gordon,AJ, Burns,PA, Zielenska,M, van der Vliet,GM, Glickman,BW. Mutational specificity of alkylating agents and the influence of DNA repair. Environ.Mol.Mutagen. 1990;15:107-122.
211. Waber,P, Dlugosz,S, Cheng,QC, Truelson,J, Nisen,PD. Genetic alterations of chromosome band 9p21-22 in head and neck cancer are not restricted to p16INK4a. Oncogene. 1997;15:1699-1704.
212. Tripathi,BA, Banerjee,S, Chunder,N et al. Differential alterations of the genes in the CDKN2A-CCND1-CDK4-RB1 pathway are associated with the development of head and neck squamous cell carcinoma in Indian patients. J Cancer Res Clin.Oncol. 2003;129:642-650.
213. Stoll,C, Baretton,G, Lohrs,U. The influence of p53 and associated factors on the outcome of patients with oral squamous cell carcinoma. Virchows Arch. 1998;433:427-433.
214. Bond,GL, Hu,W, Bond,EE et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119:591-602.
215. Jones,SN, Hancock,AR, Vogel,H, Donehower,LA, Bradley,A. Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc.Natl.Acad Sci.U.S.A. 1998;95:15608-15612.
216. Ganguli,G, Abecassis,J, Wasylyk,B. MDM2 induces hyperplasia and premalignant lesions when expressed in the basal layer of the epidermis. EMBO J. 2000;19:5135-5147.
217. Hong,Y, Miao,X, Zhang,X et al. The role of P53 and MDM2 polymorphisms in the risk of esophageal squamous cell carcinoma. Cancer Res. 2005;65:9582-9587.
218. Dazard,JE, Piette,J, Basset-Seguin,N, Blanchard,JM, Gandarillas,A. Switch from p53 to MDM2 as differentiating human keratinocytes lose their proliferative potential and increase in cellular size. Oncogene. 2000;19:3693-3705.
219. Myers,JN, Greenberg,JS, Mo,V, Roberts,D. Extracapsular spread. A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer. 2001;92:3030-3036.
220. Carter,RL, Barr,LC, O'Brien,CJ, Soo,KC, Shaw,HJ. Transcapsular spread of metastatic squamous cell carcinoma from cervical lymph nodes. Am J Surg. 1985;150:495-499.
221. Agarwal,S, Mathur,M, Srivastava,A, Ralhan,R. MDM2/p53 co-expression in oral premalignant and malignant lesions: potential prognostic implications. Oral Oncol. 1999;35:209-216.
222. Zhou,G, Zhai,Y, Cui,Y et al. MDM2 promoter SNP309 is associated with risk of occurrence and advanced lymph node metastasis of nasopharyngeal carcinoma in Chinese population. Clin.Cancer Res. 2007;13:2627-2633.
223. Zhang,L, Hill,RP. Hypoxia enhances metastatic efficiency by up-regulating Mdm2 in KHT cells and increasing resistance to apoptosis. Cancer Res. 2004;64:4180-4189.
224. Zietz,C, Rossle,M, Haas,C et al. MDM-2 oncoprotein overexpression, p53 gene mutation, and VEGF up-regulation in angiosarcomas. Am.J Pathol. 1998;153:1425-1433.
225. Takahashi,Y, Kitadai,Y, Bucana,CD, Cleary,KR, Ellis,LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995;55:3964-3968.
226. Ozdemir,E, Kakehi,Y, Okuno,H, Habuchi,T, Okada,Y, Yoshida,O. Strong correlation of basement membrane degradation with p53 inactivation and/or MDM2 overexpression in superficial urothelial carcinomas. J Urol. 1997;158:206-211.
227. Michael,D, Oren,M. The p53-Mdm2 module and the ubiquitin system. Semin.Cancer Biol. 2003;13:49-58.
228. Brennan,P. Gene-environment interaction and aetiology of cancer: what does it mean and how can we measure it? Carcinogenesis. 2002;23:381-387.
229. de Oliveira,LR, Ribeiro-Silva,A, Zucoloto,S. Prognostic impact of p53 and p63 immunoexpression in oral squamous cell carcinoma. J Oral Pathol.Med. 2007;36:191-197.
230. Gonzalez-Moles,MA, Galindo,P, Gutierrez-Fernandez,J et al. P53 protein expression in oral squamous cell carcinoma. survival analysis. Anticancer Res. 2001;21:2889-2894.
231. Ralhan,R, Sandhya,A, Meera,M, Bohdan,W, Nootan,SK. Induction of MDM2-P2 transcripts correlates with stabilized wild-type p53 in betel- and tobacco-related human oral cancer. Am J Pathol. 2000;157:587-596.
232. Liu,CJ, Chang,KW, Chao,SY et al. The molecular markers for prognostic evaluation of areca-associated buccal squamous cell carcinoma. J Oral Pathol Med. 2004;33:327-334.
233. Santarosa,M, Ashworth,A. Haploinsufficiency for tumour suppressor genes: when you don't need to go all the way. Biochim.Biophys.Acta. 2004;1654:105-122.
234. Kondo,S, Barnett,GH, Hara,H, Morimura,T, Takeuchi,J. MDM2 protein confers the resistance of a human glioblastoma cell line to cisplatin-induced apoptosis. Oncogene. 1995;10:2001-2006.
235. Agarwal,S, Mathur,M, Srivastava,A, Ralhan,R. MDM2/p53 co-expression in oral premalignant and malignant lesions: potential prognostic implications. Oral Oncol. 1999;35:209-216.
236. Vassilev,LT, Vu,BT, Graves,B et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844-848.
237. Chene,P. Inhibition of the p53-MDM2 interaction: targeting a protein-protein interface. Mol.Cancer Res. 2004;2:20-28.
238. Ruggeri,BA, Huang,L, Wood,M, Cheng,JQ, Testa,JR. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol.Carcinog. 1998;21:81-86.
239. Miller,CT, Moy,JR, Lin,L et al. Gene amplification in esophageal adenocarcinomas and Barrett's with high-grade dysplasia. Clin.Cancer Res. 2003;9:4819-4825.
240. Massion,PP, Taflan,PM, Shyr,Y et al. Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression. Am.J Respir.Crit Care Med. 2004;170:1088-1094.
241. Wu,G, Xing,M, Mambo,E et al. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res. 2005;7:R609-R616.
242. Wu,G, Mambo,E, Guo,Z et al. Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J Clin.Endocrinol.Metab. 2005;90:4688-4693.
243. Sticht,C, Hofele,C, Flechtenmacher,C et al. Amplification of Cyclin L1 is associated with lymph node metastases in head and neck squamous cell carcinoma (HNSCC). Br.J Cancer. 2005;92:770-774.
244. Nakayama,K, Nakayama,N, Kurman,RJ et al. Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biol.Ther. 2006;5:779-785.
245. Bertelsen,BI, Steine,SJ, Sandvei,R, Molven,A, Laerum,OD. Molecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation. Int.J Cancer. 2006;118:1877-1883.
246. Tripathi,BA, Banerjee,S, Chunder,N et al. Differential alterations of the genes in the CDKN2A-CCND1-CDK4-RB1 pathway are associated with the development of head and neck squamous cell carcinoma in Indian patients. J Cancer Res Clin.Oncol. 2003;129:642-650.
247. Matsuda,H, Konishi,N, Hiasa,Y et al. Alterations of p16/CDKN2, p53 and ras genes in oral squamous cell carcinomas and premalignant lesions. J Oral Pathol Med. 1996;25:232-238.
248. Sakata,K. Alterations of tumor suppressor genes and the H-ras oncogene in oral squamous cell carcinoma. J Oral Pathol Med. 1996;25:302-307.
249. Yakushiji,T, Noma,H, Shibahara,T et al. Analysis of a role for p16/CDKN2 expression and methylation patterns in human oral squamous cell carcinoma. Bull.Tokyo Dent Coll. 2001;42:159-168.
250. Poi,MJ, Yen,T, Li,J et al. Somatic INK4a-ARF locus mutations: a significant mechanism of gene inactivation in squamous cell carcinomas of the head and neck. Mol.Carcinog. 2001;30:26-36.
251. Haddad,RI, Shin,DM. Recent advances in head and neck cancer. N.Engl.J Med. 2008;359:1143-1154.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊