研究背景：癌症的形成常常是由於腫瘤抑制基因 (tumor suppressor genes, TSGs) 不表現，或是致癌基因 (oncogenes) 過度活化所造成，因此利用分佈在基因體的微衛星序列 (microsatellite markers)，針對基因體進行異質性喪失 (loss of heterozygosity, LOH) 分析，可以協助我們尋找未知的腫瘤抑制基因。大部分的肺癌組織都有很高的對偶基因缺失頻率 (fractional allelic loss, FAL)，顯示肺癌組織的基因體經常發生DNA缺失，這可能意味著癌細胞的DNA雙股斷裂 (DNA double-strand break, DSB) 修補機制效率不佳，無法將DNA雙股斷裂做適當的修復。細胞中的DNA雙股斷裂修補機制有兩個，分別是同源染色體重組路徑 (homologous recombination pathway, HR) 和非同源染色體末端接合路徑 (non-homologous end-joining pathway, NHEJ)。過去許多研究發現，基因多型性的差異會在某種程度上影響基因的功能或效率，導致不同的疾病發生敏感性，因此我們推測DNA雙股斷裂修補基因的基因多型性可能會影響肺癌的發生風險。 目的與方法：在LOH分析中，本研究使用112個微衛星序列針對84個非小細胞肺癌 (non-small cell lung cancer, NSCLC) 病人進行基因體缺失分析，並且定義最小缺失區域 (minimal deletion region, MDR)，以尋找和肺癌發生相關的腫瘤抑制基因。另外，我們針對NHEJ路徑中的四個基因：Ku70、Ku80、Ligase IV和XRCC4，進行單一核苷酸多型性 (single nucleotide polymorphism, SNP) 分析，以瞭解基因型對於肺癌發生敏感性的影響，並分析這四個基因之間是否有交互作用 (joint effect)。 結果：肺腺癌 (adenocarcinoma, AD) 和鱗狀上皮肺癌 (squamous carcinoma, SQ) 的LOH頻率分別是48%和42%。我們還發現25個MDRs，平均長度是5.18 cM，在AD和SQ中，分別有12和13個MDRs。其中MDRA7p1 (D7S1818-D7S506, 7p12.1-7p12.3) 的缺失和AD有關，而MDRS9p1 (D9S2169-D9S286, 9p24.1-9p24.3) 的缺失則是和SQ及抽菸有關。在SNP分析部分，Ku70和Ku80的基因型分佈在肺癌病人及無癌症族群間沒有顯著的差異 (P>0.05, multivariate logistic regression model)；但是我們發現當個體在Ligase IV (G3539A, Thr9Ile) 帶有高風險基因型 (A/A and A/G) 時，其得肺癌的危險比會明顯的提高 (adjusted odds ratio, aOR=1.64, 95% confidence interval, 95% CI=1.03-2.62, adjusted P=0.038)。此外，當個體在XRCC4 (G275626A, splice-site) 帶有高風險基因型 (G/G) 時，也會有較高的肺癌發生風險 aOR=2.38, 95% CI=1.05-5.76, adjusted P=0.043)。我們還發現在Ku70和Ku80之間，以及Ligase IV和XRCC4都有交互作用的存在，這樣的交互作用會使該個體的肺癌發生風險提高為一般人的4.65倍 (95% CI=1.19-24.08, adjusted P=0.040) 和8.75倍 (95% CI=2.27-57.77, adjusted P=0.006)。 結論：LOH分析以及MDRs的定義，將有利於尋找和肺癌發生有關的基因。SNP的分析，則讓我們瞭解NHEJ基因的基因多型性以及基因之間的交互作用，確實會影響肺癌發生敏感性。

Background: Most tumor suppressor genes (TSGs) are recessive. Both copies of TSGs need to be inactivated for losing their biological function. One allele may be inactivated by point mutation and methylation change. The other is frequently inactivated by a large deletion involving the gene of interest as well as adjacent stretches of DNA. Thus, searches for genomic regions frequently deleted by loss of heterozygosity (LOH) in cancer have helped to identify or confirm the location of several TSGs. In addition, lung cancer cells frequently exhibit marked chromosome instability such as high fractional allelic loss (FAL, an indication of genomic instability). We then postulated that genetic polymorphism of the double strand-break repair (DSBR) genes, Ku70, Ku80, Ligase IV, and XRCC4, may involve in lung cancer susceptibility. Purposes and Methods: To define the minimal deletion regions (MDRs) that may contain TSGs, we used 112 microsatellite markers to perform LOH analysis in tumors and corresponding normal tissues from 48 adenocarcinomas (ADs) and 36 squamous carcinomas (SQs) lung cancer patients. In addition, we investigated the frequency of four NHEJ (non-homologous end-joining) pathway genes Ku70 (C217G), Ku80 (G92504A), Ligase IV (G3539A, Thr9Ile), and XRCC4 (G275626A, splice-site) polymorphisms in 151 lung cancer patients and 162 cancer-free individuals. The joint effects of these four genes contributed to an increased cancer risk were also analyzed. Results: The average LOH frequency was 48% in AD and 42% in SQ. In addition, 12 MDRs and 13 MDRs were revealed in AD and SQ, respectively. The data suggested that different mechanisms may be involved in the development of AD and SQ. The average interval of 25 MDRs was 5.18 cM. We found that the loss of MDRA7p1 (D7S1818-D7S506, 7p12.1-7p12.3) was associated with AD, and the loss of MDRS9p1 (D9S2169-D9S286, 9p24.1-9p24.3) was associated with SQ and smoking. Furthermore, stage-specific and common deletion markers were identified, suggesting their role in tumor progression. Several candidate genes were annotated by the web-search tools and they can be target genes for further analyses. There was no significant difference in the genotype distribution of Ku70 (C217G), Ku80 (G92504A) polymorphism between lung cancer patients and cancer-free controls (P>0.05, multivariate logistic regression model). However, we found that patients with homozygous or heterozygous variant genotype (A/A or A/G) of Ligase IV (G3539A, Thr9Ile) polymorphism had a tendency to be associated with lung cancer risk (adjusted odds ratio, aOR=1.64, 95% confidence interval, CI=1.03-2.62, adjusted P=0.038). The patients with homozygous variant genotype (G/G) of XRCC4 (G275626A, splice-site) polymorphism also showed a significantly increase lung cancer risk (aOR=2.38, 95% CI=1.05-5.76, adjusted P=0.043). In addition, we found that the G/G frequency of XRCC4 was significant higher in high FAL patients than low FAL patients. (adjusted P=0.016). Furthermore, the joint effect was found between Ku70 and Ku80 as well as Ligase IV and XRCC4. The increased risk of developing lung cancer were 4.65 (95% CI=1.19-24.08, adjusted P=0.040) and 8.75 (95% CI=2.27-57.77, adjusted P=0.006), respectively, when patients harboring two putative high-risk genotypes in these genes. Conclusions: The LOH analysis and definition of MDRs can potentially be used for the clinical association study and the cloning of new TSGs whose aberration contributes to lung tumorigenesis. In addition, the polymorphic results suggest that the polymorphism in four NHEJ genes may be associated with the susceptibility to lung cancer. Our data provide new evidence that the NHEJ putative risk alleles may have a joint effect on the genomic instability of lung cancer.

1. Bains MS, 1991. Surgical treatment of lung cancer. Chest 100: 826-837.
2. Bair EL, Chen ML, McDaniel K, Sekiguchi K, Cress AE, Nagle RB, Bowden GT, 2005. Membrane type 1 matrix metalloprotease cleaves laminin-10 and promotes prostate cancer cell migration. Neoplasia 7: 380-389.
3. Beckman G, Birgander R, Själander A, Saha N, Holmberg PÅ, Kivelä A, Beckman L, 1994. Is p53 polymorphism maintained by natural selection? Hum Hered 44: 266-270.
4. Ben-Omran TI, Cerosaletti K, Concannon P, Weitzman S, Nezarati MM, 2005. A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet A 137: 283-287.
5. Bertinato J, Tomlinson JJ, Schild-Poulter C, Hache RJ, 2003. Evidence implicating Ku antigen as a structural factor in RNA polymerase II-mediated transcription. Gene 302: 53-64.
6. Bhattacharya N, Chunder N, Basu D, Roy A, Mandal S, Majumder J, Roychowdhury S, Panda CK, 2004. Three discrete areas within the chromosomal 8p21.3-23 region are associated with the development of breast carcinoma of Indian patients. Exp Mol Pathol 76: 264-271.
7. Borczuk AC, Gorenstein L, Walter KL, Assaad AA, Wang L, and Powell CA, 2003. Non-small-cell lung cancer molecular signatures recapitulate lung developmental pathways. Am J Pathol 163: 1949-1960.
8. Bosotti R, Isacchi A, and Sonnhammer EL, 2000. FAT: a novel domain in PIK-related kinase. Trends Biochem Sci 25: 225-227.
9. Bryans M, Valenzano MC, and Stamato TD, 1999. Absence of DNA ligase IV protein in XR-1 cells: evidence for stabilization by XRCC4. Mutat Res 433: 53-58.
10. Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC, White RL, 1983. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305: 779-784.
11. Chai W, Ford LP, Lenertz L, Wright WE, Shay JW, 2002. Human Ku70/80 associates physically with telomerase through interaction with hTERT. J Biol Chem 277: 47242-47247.
12. Chan DW, Chen BP, Prithivirajsingh S, Kurimasa A, Story MD, Qin J, Chen DJ, 2002. Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. Genes Dev 16: 2333-2338.
13. Chatterjee A, Pulido HA, Koul S, Beleno N, Perilla A, Posso H, Manusukhani M, Murty VV, 2001. Mapping the sites of putative tumor suppressor genes at 6p25 and 6p21.3 in cervical carcinoma: occurrence of allelic deletions in precancerous lesions. Cancer Res 61: 2119-2123.
14. Chan DW, Ye R, Veillette CJ, Lees-Miller SP, 1999. DNA-dependent protein kinase phosphorylation site in Ku 70/80 heterodimer. Biochemistry 38: 1819-1828.
15. Chen CJ, Wu HY, Chuang YC, Chang AS, Luh KT, Chao HH, Chen KY, Chen SG, Lai GM, and Huang HH, 1990. Epidemiologic characteristics and multiple risk factors of lung cancer in Taiwan. Anticancer Res 10: 971-976.
16. Chen JT, Chen YC, Wang YC, Tseng RC, Chen CY, 2002. Alteration of the p16INK4A gene in resected non-small cell lung tumors and exfoliated cells within sputum. Int J Cancer 98: 724-731.
17. Chmara M, Wozniak A, Ochman K, Kobierska G, Dziadziuszko R, Sosinska-Mielcarek K, Jassem E, Skokowski J, Jassem J, Limon J, 2004. Loss of heterozygosity at chromosomes 3p and 17p in primary non-small cell lung cancer. Anticancer Res 24: 4259-4263.
18. Critchlow SE, Bowater RP, and Jackson SP, 1997. Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV. Curr Biol 7: 588-598.
19. Dallol A, Da Silva NF, Viacava P, Minna JD, Bieche I, Maher ER, Latif F, 2002. SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers. Cancer Res 62: 5874-5880.
20. Dallol A, Krex D, Hesson L, Eng C, Maher ER, Latif F, 2003a. Frequent epigenetic inactivation of the SLIT2 gene in gliomas. Oncogene 22: 4611-4616.
21. Dallol A, Morton D, Maher ER, Latif F, 2003b. SLIT2 axon guidance molecule is frequently inactivated in colorectal cancer and suppresses growth of colorectal carcinoma cells. Cancer Res 63: 1054-1058.
22. Department of Health, The executive Yuan, Republic of China. General Health Statistics, 2006. In: Health and Vital Statistics, Republic of China. R. O. C. Press, Taipei, http://www.doh.gov.tw/statistic/index.htm
23. Douglas P, Sapkota GP, Morrice N, Yu Y, Goodarzi AA, Merkle D, Meek K, Alessi DR, Lees-Miller SP, 2002. Identification of in vitro and in vivo phosphorylation sites in the catalytic subunit of the DNA-dependent protein kinase. Biochem J 368: 243-251.
24. Dynan WS and Yoo S, 1998. Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. Nucleic Acids Res 26: 1551-1559.
25. Essers J, van Steeg H, de Wit J, Swagemakers SM, Vermeij M, Hoeijmakers JH, Kanaar R, 2000. Homologous and non-homologous recombination differentially affect DNA damage repair in mice. EMBO J 19: 1703-1710.
26. Fearon ER, 1997. Human cancer syndromes: clues to the origin and nature of cancer. Science 278: 1043-1050.
27. Field JK, Neville EM, Stewart MP, Swift A, Liloglou T, Risk JM, Ross H, Gosney JR, Donnelly RJ, 1996. Fractional allele loss data indicate distinct genetic populations in the development of non-small-cell lung cancer. Br J Cancer 74: 1968-1974.
28. Foster RE, Nnakwe C, Woo L, Frank KM, 2006. Monoubiquitination of the nonhomologous end joining protein XRCC4. Biochem Biophys Res Commun 341: 175-183.
29. Fu YP, Yu JC, Cheng TC, Lou MA, Hsu GC, Wu CY, Chen ST, Wu HS, Wu PE, Shen CY, 2003. Breast cancer risk associated with genotypic polymorphism of the nonhomologous end-joining genes: a multigenic study on cancer susceptibility. Cancer Res 63: 2440-2446.
30. Gell D and Jackson SP, 1999. Mapping of protein-protein interactions within the DNA-dependent protein kinase complex. Nucleic Acids Res 27: 3494-3502.
31. Girard L, Zochbauer-Meller S, Virmani AK, Gazdar AF, Minna JD, 2000. 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 60: 4894-4906.
32. Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M, Lieber MR, 1997. Activity of DNA ligase IV simulated by complex formation with XRCC4 protein in mammalian cells. Nature 388: 492-495.
33. Grepmeier U, Dietmaier W, Merk J, Wild PJ, Obermann EC, Pfeifer M, Hofstaedter F, Hartmann A, Woenckhaus M, 2005. Deletions at chromosome 2q and 12p are early and frequent molecular alterations in bronchial epithelium and NSCLC of long-term smokers. Int J Oncol 27: 481-488.
34. Hibino S, Shibuya M, Engbring JA, Mochizuki M, Nomizu M, Kleinman HK, 2004. Identification of an active site on the laminin alpha5 chain globular domain that binds to CD44 and inhibits malignancy. Cancer Res 64: 4810-4816.
35. Hollander MC, Philburn RT, Patterson AD, Velasco-Miguel S, Friedberg EC, Linnoila RI, Fornace AJ Jr, 2005. Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis. Proc Natl Acad Sci U S A 102: 13200-13205.
36. Hsu HL, Gilley D, Galande SA, Hande MP, Allen B, Kim SH, Li GC, Campisi J, Kohwi-Shigematsu T, Chen DJ, 2000. Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev 14: 2807-2812.
37. Huang SP, Huang CY, Wu WJ, Pu YS, Chen J, Chen YY, Yu CC, Wu TT, Wang JS, Lee YH, Huang JK, Huang CH, Wu MT, 2006. Association of vitamin D receptor FokI polymorphism with prostate cancer risk, clinicopathological features and recurrence of prostate specific antigen after radical prostatectomy. Int J Cancer 119: 1902-1907.
38. Iwamoto Y, Robey FA, Graf J, Sasaki M, Kleinman HK, Yamada Y, Martin GR, 1987. YIGSR, a synthetic laminin pentapeptide, inhibits experimental metastasis formation. Science 238: 1132-1134.
39. Jackson SP, 2002. Sensing and repairing DNA double-strand breaks. Carcinogenesis 23: 687-696.
40. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ, 2004. Cancer statistics 2004. CA Cancer J Clin 54: 8-29.
41. Jin S, Kharbanda S, Mayer B, Kufe D, Weaver DT, 1997. Binding of Ku and c-Abl at the kinase homology region of DNA-dependent protein kinase catalytic subunit. J Biol Chem 272: 24763-24766.
42. Jin S and Weaver DT, 1997. Double-strand break repair by Ku70 requires heterodimerization with Ku80 and DNA binding functions. EMBO J 16: 6874-6885.
43. Johnson RD and Jasin M, 2000. Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells. EMBO J 19: 3398-3407.
44. Jou YS, Lee CS, Chang YH, Hsiao CF, Chen CF, Chao CC, Wu LS, Yeh SH, Chen DS, Chen PJ, 2004. Clustering of minimal deleted regions reveals distinct genetic pathways of human hepatocellular carcinoma. Cancer Res 64: 3030-3036.
45. Junop MS, Modesti M, Guarne A, Ghirlando R, Gellert M, Yang W, 2000. Crystal structure of the XRCC4 DNA repair protein and implications for end joining. EMBO J 19: 5962-5970.
46. Karran P, 2000. DNA double strand break repair in mammalian cells. Curr Opin Genet Dev 10:144-150.
47. Ke H, Pei J, Ni Z, Xia H, Qi H, Woods T, Kelekar A, Tao W, 2004. Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-x(L). Exp Cell Res 298: 329-338.
48. Kikkawa Y, Sanzen N, Sekiguchi K, 1998. Isolation and characterization of laminin-10/11 secreted by human lung carcinoma cells. laminin-10/11 mediates cell adhesion through integrin alpha3 beta1. J Biol Chem 273: 15854-15859.
49. Kohno T and Yokota J, 1999. How many tumor suppressor genes are involved in human lung carcinoma? Carcinogenesis 20: 1403-1410.
50. Koike M, 2002. Dimerization, translocation and localization of Ku70 and Ku80 proteins. J Radiat Res 43: 223-236.
51. Lee KJ, Dong X, Wang J, Takeda Y, Dynan WS, 2002. Identification of human autoantibodies to the DNA ligase IV/XRCC4 complex and mapping of an autoimmune epitope to a potential regulatory region. J Immunol 169: 3413-3421.
52. Li Z, Otevrel T, Gao Y, Cheng HL, Seed B, Stamato TD, Taccioli GE, Alt FW, 1995. The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination. Cell 83: 1079-1089.
53. Lieber MR, Ma Y, Pannicke U, Schwarz K, 2003. Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 4: 712-720.
54. Mahajan KN, Nick McElhinny SA, Mitchell BS, Ramsden DA, 2002. Association of DNA polymerase mu (pol mu) with Ku and ligase IV: role for pol mu in end-joining double-strand break repair. Mol Cell Biol 22: 5194-5202.
55. Mao L, 2002. Recent advances in the molecular diagnosis of lung cancer. Oncogene 21: 6960-6969.
56. Massion PP and Carbone DP, 2003. The molecular basis of lung cancer: molecular abnormalities and therapeutic implications. Repair Res 4: 12.
57. Matsumoto S, Kasumi F, Sakamoto G, Onda M, Nakamura Y, Emi M, 1997. Detailed deletion mapping of chromosome arm 3p in breast cancers: a 2-cM region on 3p14.3-21.1 and a 5-cM region on 3p24.3-25.1 commonly deleted in tumors. Genes Chromosomes Cancer 20: 268-274.
58. Mendes-da-Silva P, Moreira A, Duro-da-Costa J, Matias D, Monteiro C, 2000. Frequent loss of heterozygosity on chromosome 5 in non-small cell lung carcinoma. Mol Pathol 53: 184-187.
59. Mendoza-Londono R, Kashork CD, Shaffer LG, Krance R, Plon SE, 2005. Acute lymphoblastic leukemia in a patient with Greig cephalopolysyndactyly and interstitial deletion of chromosome 7 del(7)(p11.2 p14) involving the GLI3 and ZNFN1A1 genes. Genes Chromosomes Cancer 42: 82-86.
60. Meuwissen R and Berns A, 2005. Mouse models for human lung cancer. Genes Dev 19: 643-664.
61. Michl P, Ramjaun AR, Pardo OE, Warne PH, Wagner M, Poulsom R, D'Arrigo C, Ryder K, Menke A, Gress T, Downward J, 2005. CUTL1 is a target of TGF(beta) signaling that enhances cancer cell motility and invasiveness. Cancer Cell 7: 521-532.
62. Munoz P, Zdzienicka MZ, Blanchard JM, Piette J, 1998. Hypersensitivity of Ku-deficient cells toward the DNA topoisomerase II inhibitor ICRF-193 suggests a novel role for Ku antigen during the G2 and M phases of the cell cycle. Mol Cell Biol 18: 5797-5808.
63. Nussenzweig A, Sokol K, Burgman P, Li L, Li GC, 1997. Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: the effects of ionizing radiation on growth, survival, and development. Proc Natl Acad Sci U S A 94: 13588-13593.
64. O'Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, Gatti RA, Varon R, Oettinger MA, Neitzel H, Jeggo PA, Concannon P, 2001. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 8: 1175-1185.
65. Pastwa E and Blasiak J, 2003. Non-homologous DNA end joining. Acta Biochim Pol 50: 891-908.
66. Perinchery G, Bukurov N, Nakajima K, Chang J, Li LC, Dahiya R, 1999. High frequency of deletion on chromosome 9p21 may harbor several tumor-suppressor genes in human prostate cancer. Int J Cancer 83: 610-614.
67. Riballo E, Critchlow SE, Teo SH, Doherty AJ, Priestley A, Broughton B, Kysela B, Beamish H, Plowman N, Arlett CF, Lehmann AR, Jackson SP, Jeggo PA, 1999. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr Biol 9: 699-702.
68. Shao J, Li Y, Li H, Wu Q, Hou J, Liew C, 2000. Deletion of chromosomes 9p and 17 associated with abnormal expression of p53, p16/MTS1 and p15/MTS2 gene protein in hepatocellular carcinomas. Chin Med J 113: 817-822.
69. Shen CY, Yu JC, Lo YL, Kuo CH, Yue CT, Jou YS, Huang CS, Lung JC, Wu CW, 2000. 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 Res 60: 3884-3892.
70. Sherwood JB, Shivapurkar N, Lin WM, Ashfaq R, Miller DS, Gazdar AF, Muller CY, 2000. Chromosome 4 deletions are frequent in invasive cervical cancer and differ between histologic variants. Gynecol Oncol 79: 90-96.
71. Shin JH, Kang SM, Kim YS, Shin DH, Chang J, Kim SK, Kim SK, 2005. Identification of tumor suppressor loci on the long arm of chromosome 5 in pulmonary large cell neuroendocrine carcinoma. Chest 128 : 2999-3003.
72. Shiseki M, Kohno T, Adachi J, Okazaki T, Otsuka T, Mizoguchi H, Noguchi M, Hirohashi S, Yokota J, 1996. Comparative allelotype of early and advanced stage non-small cell lung carcinomas. Genes Chromosomes Cancer 17: 71-77.
73. Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL, Pellegrini L, 2001. Crystal structure of an Xrcc4-DNA ligase IV complex. Nat Struct Biol 8: 1015-1019.
74. Singleton BK, Priestley A, Steingrimsdottir H, Gell D, Blunt T, Jackson SP, Lehmann AR, Jeggo PA, 1997. Molecular and biochemical characterization of xrs mutants defective in Ku80. Mol Cell Biol 17:1264-1273.
75. Singleton BK, Torres-Arzayus MI, Rottinghaus ST, Taccioli GE, Jeggo PA, 1999. The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit. Mol Cell Biol 19:3267-3277.
76. Smith GC and Jackson SP, 1999. The DNA-dependent protein kinase. Genes Dev 13: 916-934.
77. Soubeyrand S, Pope L, Pakuts B, Hache RJ, 2003. Threonines 2638/2647 in DNA-PK are essential for cellular resistance to ionizing radiation. Cancer Res 63: 1198-1201.
78. Tai AL, Mak W, Ng PK, Chua DT, Ng MY, Fu L, Chu KK, Fang Y, Qiang Song Y, Chen M, Zhang M, Sham PC, Guan XY, 2006. High-throughput loss-of-heterozygosity study of chromosome 3p in lung cancer using single-nucleotide polymorphism markers. Cancer Res 66: 4133-4138.
79. Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi H, Yamaguchi-Iwai Y, Shinohara A, Takeda S, 1998. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J 17: 5497-5508.
80. Tamura G and Satodate R, 1996. Microsatellite analysis. Nippon Rinsho 54: 928-932.
81. Vieten L, Belair CD, Savelieva L, Julicher K, Brocker F, Bardenheuer W, Schutte J, Opalka B, Reznikoff CA, 1998. Minimal deletion of 3p13-->14.2 associated with immortalization of human uroepithelial cells. Genes Chromosomes Cancer 21: 39-48.
82. Virmani AK, Fong KM, Kodagoda D, McIntire D, Hung J, Tonk V, Minna JD, Gazdar AF, 1998. Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types. Genes Chromosomes Cancer 21: 308-319.
83. Walker JR, Corpina RA, Goldberg J, 2001. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412: 607-614.
84. Weston A, Perrin LS, Forrester K, Hoover RN, Trump BF, Harris CC, Caporaso NE, 1992. Allelic frequency of a p53 polymorphism in human lung cancer. Cancer Epidemiol Biomarkers Prev 1: 481-483.
85. WHO, 1982. Histological typing of lung tumors. Am J Clin Pathol 77: 123-126.
86. Wieland I, Bohm M, Arden KC, Ammermuller T, Bogatz S, Viars CS, Rajewsky MF, 1996. Allelic deletion mapping on chromosome 5 in human carcinomas. Oncogene 12: 97-102.
87. Wu X and Lieber MR, 1996. Protein-protein and protein-DNA interaction regions within the DNA end-binding protein Ku70-Ku86. Mol Cell Biol 16: 5186-5193.
88. Yu CY, Pan KF, Xing DY, Liang G, Tan W, Zhang L, Lin D, 2002. Correlation between a single nucleotide polymorphism in matrix metalloproteinase-2 promoter and risk of lung cancer. Cancer Res 62: 6430-6433.
89. Yu Y, Wang W, Ding Q, Ye R, Chen D, Merkle D, Schriemer D, Meek K, Lees-Miller SP, 2003. DNA-PK phosphorylation sites in XRCC4 are not required for survival after radiation or for V(D)J recombination. DNA Repair 2: 1239-1252.
90. Zabarovsky ER, Lerman MI, Minna JD, 2002. Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 21: 6915-6935.
91. Zeng WR, Scherer SW, Koutsilieris M, Huizenga JJ, Filteau F, Tsui LC, Nepveu A, 1997. Loss of heterozygosity and reduced expression of the CUTL1 gene in uterine leiomyomas. Oncogene 14: 2355-2365.