自1982年起，癌症即為台灣地區十大死亡原因之首位，而肺癌在台灣地區分別佔女性及男性癌症死亡率的首位及第二位。儘管目前醫學已相當進步，但對於肺癌分子致癌機制仍未完全釐清。目前所知，癌症形成的原因，部分是由於基因變異造成，如致癌基因 (Oncogene)活性過度增加、腫瘤抑制基因 (Tumor suppressor gene)失去活性或DNA修補基因變異所導致。由於DNA雙股斷裂 (Double-strand breaks, DSBs)對於基因體穩定性是很嚴重的傷害，因為它會導致染色體的不正常情形，如基因異質性喪失 (Loss of heterozygosity, LOH)；因此，我們想要了解這些DNA雙股斷裂修補基因(DSBR genes)若發生變異，是否參與台灣地區非小細胞肺癌 (non-small cell lung cancer, NSCLC)病人肺癌形成。在本研究中，檢查了三個DSBs修補基因BRCA1、BRCA2和XRCC5之DNA、RNA和蛋白質層面的變異情形；BRCA1與BRCA2參與homologous recombination (HR)，而XRCC5參與non-homologous end-joining (NHEJ)。研究結果發現在BRCA1基因部分：87位NSCLC病人發生LOH頻率為26.3% (20/76)，啟動子高度甲基化頻率為31% (27/87)，而其蛋白質和RNA變異頻率分別為28.7% (25/87)和29.9% (26/87)。在BRCA2部分：44.9% (31/69)病人發生LOH，啟動子高度甲基化頻率為39.1% (34/87)，而36.8% (32/87)的病人其RNA有顯著下降的情形，並且其變異與癌症型式為肺腺癌 (lung adenocarcinoma) (P=0.017)與年齡較大 (P=0.035)的病人有關。在XRCC5部分：37.3% (25/67)病人發生LOH，啟動子高度甲基化頻率為21.8% (19/87)，18.4% (16/87)蛋白質表現降低，27.6% (24/87)病人RNA表現下降，且其變異與癌症型式為肺上皮細胞癌 (squamous carcinoma, SQ) (P=0.031)和有吸菸 (P=0.043)的病患較有關。綜觀以上，研究中的BRCA1、BRCA2和XRCC5，任一蛋白質層面 (除BRCA2以mRNA計)發生變異的有54人，佔總研究人數87人的62.1%，並且發現在87位病人中，此三基因同時發生變異的只有4位，暗示HR與NHEJ在肺癌形成的的過程中，這二個修補路徑均具有相當的重要性。另外，我們還檢查了DNA傷害反應誘發p53蛋白表現情形，發現87位NSCLC病人中，52.8% (46/87)病人的p53有不正常累積的現象，同時發現這些病人多為SQ型式 (P=0.006)，並多屬於肺癌晚期 (P=0.044)的病患。
本研究為首篇對DNA雙股斷裂修補基因：BRCA1、BRCA2和XRCC5與非小細胞肺癌形成，做一完整的DNA、RNA和蛋白質之研究，而研究結果亦顯示：DNA雙股斷裂修補基因變異，在非小細胞肺癌的形成中扮演重要角色。

BACKGROUND: Since 1982, lung cancer is the leading and second cause of cancer deaths among women and men in Taiwan, respectively. Although the medical science makes rapid progress, the molecular mechanisms involved in lung tumorigenesis in Taiwan remain poorly defined. Alterations of oncogenes, tumor suppressor genes or DNA repair genes have been shown to involve in the multi-steps carcinogenesis of human cancer. Double-strand breaks in DNA are serious threats to genome integrity because they can result in chromosomal aberrations, such as loss of heterozygosity (LOH). AIM: The purpose of this study is to identify the molecular mechanism of alterations of the DNA double-strand break repair (DSBR) genes, BRCA1, BRCA2, and XRCC5, involved in non-small cell lung cancer (NSCLC) tumorigenesis in Taiwan. RESULTS: We found that the frequency of BRCA1 LOH and promoter hypermethylation was 26.3% (20/76) and 31% (27/87), respectively. In addition, 28.7% (25/87) and 29.9% (26/87) NSCLC patients had decreased or loss of BRCA1 protein and mRNA expression, respectively. With regard to BRCA2 gene alteration analyses, we found that the frequency of BRCA2 LOH and promoter hypermethylation was 44.9% (31/69) and 39.1% (34/87), respectively. Note that 36.8% (32/87) NSCLC patients had decreased or loss of BRCA2 mRNA expression. The abnormal BRCA2 expression was found more frequently in adenocarcinoma (P=0.017) and old patients (P=0.035). In addition, we found that the frequency of XRCC5 LOH and promoter hypermethylation was 37.3% (25/67) and 21.8% (19/87), respectively. There were 18.4% (16/87) and 27.6% (24/87) of NSCLC patients had decreased or loss of XRCC5 protein and mRNA expression, respectively. The abnormal XRCC5 expression was found more frequently in squamous carcinoma (SQ, P=0.031) and smoking (P=0.043) patients. Among the 87 NSCLC patients analyzed, alterations in at least one of the DSBR genes were 62.1% (54/87). In addition, we analyzed the protein expression of the damage response gene, p53. It was found that 52.8% (46/87) NSCLC patients with p53 overexpression, and most of them were SQ (P=0.006) and late stage (P=0.044) patients. CONCLUSION: The study was the first report which comprehensively examines the alteration of the DSBR genes, BRCA1, BRCA2, and XRCC5 at DNA, RNA and protein levels in lung tumorigenesis. Our data indicate that the alterations in DSBR involve in NSCLC tumorigenesis in Taiwan.

1. Chen, C. J., You, S. L., Lin, L. H., Hsu, W. L., and Yang, Y. W. Cancer epidemiology and control in Taiwan: a brief review. Jpn J Clin Oncol, 32: S66-81., 2002.
2. Tammemagi, C. M., Neslund-Dudas, C., Simoff, M., and Kvale, P. Smoking and lung cancer survival: the role of comorbidity and treatment. Chest, 125: 27-37., 2004.
3. Honma, H. Classification of lung cancer by disease stage, symptom type and histological type. Naika, 18: 832-836., 1966.
4. De Vuyst, P., Dumortier, P., Jacobovitz, D., Emri, S., Coplu, L., and Baris, Y. I. Environmental asbestosis complicated by lung cancer. Chest, 105: 1593-1595., 1994.
5. Samet, J. M. Environmental causes of lung cancer: what do we know in 2003? Chest, 125: 80S-83S., 2004.
6. Vencevicius, V. Surgical approach in treatment of associated lung pathology - lung cancer at tuberculosis. Medicina (Kaunas), 40: 149-151., 2004.
7. van der Wal, A. M., Huizinga, E., Orie, N. G., Sluiter, H. J., and de Vries, K. Cancer and chronic non-specific lung disease (C.N.S.L.D.). Scand J Respir Dis., 47(3): 161-172., 1966.
8. Wagoner, J. K., Archer, V. E., Lundin, F. E., Jr., Holaday, D. A., and Lloyd, J. W. Radiation as the cause of lung cancer among uranum miners. N Engl J Med, 273: 181-188., 1965.
9. Lindop, P. J. and Rotblat, J. Induction of lung tumours by the action of radiation and urethane. Nature, 210: 1392-1393., 1966.
10. Sun, J. L., He, X. S., Yu, Y. H., and Chen, Z. C. Expression and structure of BNIP3L in lung cancer. Ai Zheng, 23: 8-14., 2004.
11. Sasaki, M., Sugio, K., Kuwabara, Y., Koga, H., Nakagawa, M., Chen, T., Kaneko, K., Hayashi, K., Shioyama, Y., Sakai, S., and Honda, H. Alterations of tumor suppressor genes (Rb, p16, p27 and p53) and an increased FDG uptake in lung cancer. Ann Nucl Med, 17: 189-196., 2003.
12. Sozzi, G., Pastorino, U., Moiraghi, L., Tagliabue, E., Pezzella, F., Ghirelli, C., Tornielli, S., Sard, L., Huebner, K., Pierotti, M. A., Croce, C. M., and Pilotti, S. Loss of FHIT function in lung cancer and preinvasive bronchial lesions. Cancer Res, 58: 5032-5037., 1998.
13. Wang, Y. C., Lu, Y. P., Tseng, R. C., Lin, R. K., Chang, J. W., Chen, J. T., Shih, C. M., and Chen, C. Y. Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples. J Clin Invest, 111: 887-895., 2003.
14. Khanna, K. K. and Jackson, S. P. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet, 27: 247-254., 2001.
15. Dasika, G. K., Lin, S. C., Zhao, S., Sung, P., Tomkinson, A., and Lee, E. Y. DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis. Oncogene, 18: 7883-7899., 1999.
16. Moynahan, M. E. and Jasin, M. Loss of heterozygosity induced by a chromosomal double-strand break. Proc Natl Acad Sci U S A, 94: 8988-8993., 1997.
17. Mills, K. D., Ferguson, D. O., and Alt, F. W. The role of DNA breaks in genomic instability and tumorigenesis. Immunol Rev, 194: 77-95., 2003.
18. Thacker, J. and Zdzienicka, M. Z. The mammalian XRCC genes: their roles in DNA repair and genetic stability. DNA Repair (Amst), 2: 655-672., 2003.
19. Masuda, A. and Takahashi, T. Chromosome instability in human lung cancers: possible underlying mechanisms and potential consequences in the pathogenesis. Oncogene, 21: 6884-6897., 2002.
20. Liloglou, T., Maloney, P., Xinarianos, G., Hulbert, M., Walshaw, M. J., Gosney, J. R., Turnbull, L., and Field, J. K. Cancer-specific genomic instability in bronchial lavage: a molecular tool for lung cancer detection. Cancer Res, 61: 1624-1628., 2001.
21. Shen, C. Y., Yu, J. C., Lo, Y. L., Kuo, C. H., Yue, C. T., Jou, Y. S., Huang, C. S., Lung, J. C., and Wu, C. W. 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., 2000.
22. Fu, Y. P., Yu, J. C., Cheng, T. C., Lou, M. A., Hsu, G. C., Wu, C. Y., Chen, S. T., Wu, H. S., Wu, P. E., and Shen, C. Y. Breast cancer risk associated with genotypic polymorphism of the nonhomologous end-joining genes: a multigenic study on cancer susceptibility. Cancer Res, 63: 2440-2446., 2003.
23. van Gent, D. C., Hoeijmakers, J. H., and Kanaar, R. Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet, 2: 196-206., 2001.
24. Takata, M., Sasaki, M. S., Sonoda, E., Morrison, C., Hashimoto, M., Utsumi, H., Yamaguchi-Iwai, Y., Shinohara, A., and Takeda, S. 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., 1998.
25. Essers, J., van Steeg, H., de Wit, J., Swagemakers, S. M., Vermeij, M., Hoeijmakers, J. H., and Kanaar, R. Homologous and non-homologous recombination differentially affect DNA damage repair in mice. EMBO J, 19: 1703-1710., 2000.
26. Johnson, R. D. and Jasin, M. Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells. EMBO J, 19: 3398-3407., 2000.
27. Zheng, L., Li, S., Boyer, T. G., and Lee, W. H. Lessons learned from BRCA1 and BRCA2. Oncogene, 19: 6159-6175., 2000.
28. Baumann, P. and West, S. C. Role of the human RAD51 protein in homologous recombination and double-stranded-break repair. Trends Biochem Sci, 23: 247-251., 1998.
29. Bishop, D. K., Ear, U., Bhattacharyya, A., Calderone, C., Beckett, M., Weichselbaum, R. R., and Shinohara, A. Xrcc3 is required for assembly of Rad51 complexes in vivo. J Biol Chem, 273: 21482-21488., 1998.
30. Takata, M., Sasaki, M. S., Sonoda, E., Fukushima, T., Morrison, C., Albala, J. S., Swagemakers, S. M., Kanaar, R., Thompson, L. H., and Takeda, S. The Rad51 paralog Rad51B promotes homologous recombinational repair. Mol Cell Biol, 20: 6476-6482., 2000.
31. Sung, P., Trujillo, K. M., and Van Komen, S. Recombination factors of Saccharomyces cerevisiae. Mutat Res, 451: 257-275., 2000.
32. Karran, P. DNA double strand break repair in mammalian cells. Curr Opin Genet Dev, 10: 144-150., 2000.
33. Pastwa, E. and Blasiak, J. Non-homologous DNA end joining. Acta Biochim Pol., 50: 891-908., 2003.
34. Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L. M., Ding, W., and et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science, 266: 66-71., 1994.
35. Chen, Y., Farmer, A. A., Chen, C. F., Jones, D. C., Chen, P. L., and Lee, W. H. BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res, 56: 3168-3172., 1996.
36. Koonin, E. V., Altschul, S. F., and Bork, P. BRCA1 protein products ... Functional motifs. Nat Genet, 13: 266-268., 1996.
37. Chiba, N. and Parvin, J. D. The BRCA1 and BARD1 association with the RNA polymerase II holoenzyme. Cancer Res, 62: 4222-4228., 2002.
38. Chapman, M. S. and Verma, I. M. Transcriptional activation by BRCA1. Nature, 382: 678-679., 1996.
39. Zhong, Q., Chen, C. F., Li, S., Chen, Y., Wang, C. C., Xiao, J., Chen, P. L., Sharp, Z. D., and Lee, W. H. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science, 285: 747-750., 1999.
40. Zhang, H., Somasundaram, K., Peng, Y., Tian, H., Bi, D., Weber, B. L., and El-Deiry, W. S. BRCA1 physically associates with p53 and stimulates its transcriptional activity. Oncogene, 16: 1713-1721., 1998.
41. Wang, Q., Zhang, H., Kajino, K., and Greene, M. I. BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cells. Oncogene, 17: 1939-1948., 1998.
42. Aprelikova, O. N., Fang, B. S., Meissner, E. G., Cotter, S., Campbell, M., Kuthiala, A., Bessho, M., Jensen, R. A., and Liu, E. T. BRCA1-associated growth arrest is RB-dependent. Proc Natl Acad Sci U S A, 96: 11866-11871., 1999.
43. Scully, R., Chen, J., Plug, A., Xiao, Y., Weaver, D., Feunteun, J., Ashley, T., and Livingston, D. M. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell, 88: 265-275., 1997.
44. Anderson, S. F., Schlegel, B. P., Nakajima, T., Wolpin, E. S., and Parvin, J. D. BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. Nat Genet, 19: 254-256., 1998.
45. Li, S., Chen, P. L., Subramanian, T., Chinnadurai, G., Tomlinson, G., Osborne, C. K., Sharp, Z. D., and Lee, W. H. Binding of CtIP to the BRCT repeats of BRCA1 involved in the transcription regulation of p21 is disrupted upon DNA damage. J Biol Chem, 274: 11334-11338., 1999.
46. Yu, X., Wu, L. C., Bowcock, A. M., Aronheim, A., and Baer, R. The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J Biol Chem, 273: 25388-25392., 1998.
47. Yarden, R. I. and Brody, L. C. BRCA1 interacts with components of the histone deacetylase complex. Proc Natl Acad Sci U S A, 96: 4983-4988., 1999.
48. Pao, G. M., Janknecht, R., Ruffner, H., Hunter, T., and Verma, I. M. CBP/p300 interact with and function as transcriptional coactivators of BRCA1. Proc Natl Acad Sci U S A, 97: 1020-1025., 2000.
49. Schlegel, B. P., Green, V. J., Ladias, J. A., and Parvin, J. D. BRCA1 interaction with RNA polymerase II reveals a role for hRPB2 and hRPB10alpha in activated transcription. Proc Natl Acad Sci U S A, 97: 3148-3153., 2000.
50. Zheng, L., Pan, H., Li, S., Flesken-Nikitin, A., Chen, P. L., Boyer, T. G., and Lee, W. H. Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Mol Cell, 6: 757-768., 2000.
51. Neish, A. S., Anderson, S. F., Schlegel, B. P., Wei, W., and Parvin, J. D. Factors associated with the mammalian RNA polymerase II holoenzyme. Nucleic Acids Res, 26: 847-853., 1998.
52. Hill, D. A., de la Serna, I. L., Veal, T. M., and Imbalzano, A. N. BRCA1 interacts with dominant negative SWI/SNF enzymes without affecting homologous recombination or radiation-induced gene activation of p21 or Mdm2. J Cell Biochem, 91: 987-998., 2004.
53. Bochar, D. A., Wang, L., Beniya, H., Kinev, A., Xue, Y., Lane, W. S., Wang, W., Kashanchi, F., and Shiekhattar, R. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell, 102: 257-265., 2000.
54. Gowen, L. C., Avrutskaya, A. V., Latour, A. M., Koller, B. H., and Leadon, S. A. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science, 281: 1009-1012., 1998.
55. Xu, B., Kim, S., and Kastan, M. B. Involvement of Brca1 in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol Cell Biol, 21: 3445-3450., 2001.
56. Jin, S., Zhao, H., Fan, F., Blanck, P., Fan, W., Colchagie, A. B., Fornace, A. J., Jr., and Zhan, Q. BRCA1 activation of the GADD45 promoter. Oncogene, 19: 4050-4057., 2000.
57. Liu, C. Y., Flesken-Nikitin, A., Li, S., Zeng, Y., and Lee, W. H. Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev, 10: 1835-1843., 1996.
58. Ludwig, T., Chapman, D. L., Papaioannou, V. E., and Efstratiadis, A. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev, 11: 1226-1241., 1997.
59. Xu, X., Weaver, Z., Linke, S. P., Li, C., Gotay, J., Wang, X. W., Harris, C. C., Ried, T., and Deng, C. X. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell, 3: 389-395., 1999.
60. Wooster, R., Neuhausen, S. L., Mangion, J., Quirk, Y., Ford, D., Collins, N., Nguyen, K., Seal, S., Tran, T., Averill, D., and et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science, 265: 2088-2090., 1994.
61. Siddique, H., Zou, J. P., Rao, V. N., and Reddy, E. S. The BRCA2 is a histone acetyltransferase. Oncogene, 16: 2283-2285., 1998.
62. Wong, J. M., Ionescu, D., and Ingles, C. J. Interaction between BRCA2 and replication protein A is compromised by a cancer-predisposing mutation in BRCA2. Oncogene, 22: 28-33., 2003.
63. Wong, A. K., Pero, R., Ormonde, P. A., Tavtigian, S. V., and Bartel, P. L. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2. J Biol Chem, 272: 31941-31944., 1997.
64. Chen, P. L., Chen, C. F., Chen, Y., Xiao, J., Sharp, Z. D., and Lee, W. H. The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci U S A, 95: 5287-5292., 1998.
65. Milner, J., Ponder, B., Hughes-Davies, L., Seltmann, M., and Kouzarides, T. Transcriptional activation functions in BRCA2. Nature, 386: 772-773., 1997.
66. Marmorstein, L. Y., Kinev, A. V., Chan, G. K., Bochar, D. A., Beniya, H., Epstein, J. A., Yen, T. J., and Shiekhattar, R. A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression. Cell, 104: 247-257., 2001.
67. Chen, J., Silver, D. P., Walpita, D., Cantor, S. B., Gazdar, A. F., Tomlinson, G., Couch, F. J., Weber, B. L., Ashley, T., Livingston, D. M., and Scully, R. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell, 2: 317-328., 1998.
68. Suzuki, A., de la Pompa, J. L., Hakem, R., Elia, A., Yoshida, R., Mo, R., Nishina, H., Chuang, T., Wakeham, A., Itie, A., Koo, W., Billia, P., Ho, A., Fukumoto, M., Hui, C. C., and Mak, T. W. Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev, 11: 1242-1252., 1997.
69. Wu, X. and Lieber, M. R. Protein-protein and protein-DNA interaction regions within the DNA end-binding protein Ku70-Ku86. Mol Cell Biol, 16: 5186-5193., 1996.
70. Koike, M. Dimerization, translocation and localization of Ku70 and Ku80 proteins. J Radiat Res (Tokyo), 43: 223-236., 2002.
71. Koike, M., Shiomi, T., and Koike, A. Dimerization and nuclear localization of ku proteins. J Biol Chem, 276: 11167-11173. Epub 12001 Jan 11110., 2001.
72. Osipovich, O., Durum, S. K., and Muegge, K. Defining the minimal domain of Ku80 for interaction with Ku70. J Biol Chem, 272: 27259-27265., 1997.
73. Koike, M., Ikuta, T., Miyasaka, T., and Shiomi, T. Ku80 can translocate to the nucleus independent of the translocation of Ku70 using its own nuclear localization signal. Oncogene, 18: 7495-7505., 1999.
74. Singleton, B. K., Torres-Arzayus, M. I., Rottinghaus, S. T., Taccioli, G. E., and Jeggo, P. A. The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit. Mol Cell Biol, 19: 3267-3277., 1999.
75. Mimori, T., Akizuki, M., Yamagata, H., Inada, S., Yoshida, S., and Homma, M. Characterization of a high molecular weight acidic nuclear protein recognized by autoantibodies in sera from patients with polymyositis-scleroderma overlap. J Clin Invest, 68: 611-620., 1981.
76. Hsu, H. L., Gilley, D., Galande, S. A., Hande, M. P., Allen, B., Kim, S. H., Li, G. C., Campisi, J., Kohwi-Shigematsu, T., and Chen, D. J. Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev, 14: 2807-2812., 2000.
77. Chai, W., Ford, L. P., Lenertz, L., Wright, W. E., and Shay, J. W. Human Ku70/80 associates physically with telomerase through interaction with hTERT. J Biol Chem, 277: 47242-47247, 2002.
78. Bertinato, J., Tomlinson, J. J., Schild-Poulter, C., and Hache, R. J. Evidence implicating Ku antigen as a structural factor in RNA polymerase II-mediated transcription. Gene, 302: 53-64., 2003.
79. Nussenzweig, A., Sokol, K., Burgman, P., Li, L., and Li, G. C. 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., 1997.
80. Munoz, P., Zdzienicka, M. Z., Blanchard, J. M., and Piette, J. 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., 1998.
81. Difilippantonio, M. J., Zhu, J., Chen, H. T., Meffre, E., Nussenzweig, M. C., Max, E. E., Ried, T., and Nussenzweig, A. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature, 404: 510-514., 2000.
82. Li, S. S., Tseng, H. M., Yang, T. P., Liu, C. H., Teng, S. J., Huang, H. W., Chen, L. M., Kao, H. W., Chen, J. H., Tseng, J. N., Chen, A., Hou, M. F., Huang, T. J., Chang, H. T., Mok, K. T., and Tsai, J. H. Molecular characterization of germline mutations in the BRCA1 and BRCA2 genes from breast cancer families in Taiwan. Hum Genet, 104: 201-204., 1999.
83. Ligtenberg, M. J., Hogervorst, F. B., Willems, H. W., Arts, P. J., Brink, G., Hageman, S., Bosgoed, E. A., Van der Looij, E., Rookus, M. A., Devilee, P., Vos, E. M., Wigbout, G., Struycken, P. M., Menko, F. H., Rutgers, E. J., Hoefsloot, E. H., Mariman, E. C., Brunner, H. G., and Van 't Veer, L. J. Characteristics of small breast and/or ovarian cancer families with germline mutations in BRCA1 and BRCA2. Br J Cancer, 79: 1475-1478., 1999.
84. Osorio, A., Barroso, A., Martinez, B., Cebrian, A., San Roman, J. M., Lobo, F., Robledo, M., and Benitez, J. Molecular analysis of the BRCA1 and BRCA2 genes in 32 breast and/or ovarian cancer Spanish families. Br J Cancer, 82: 1266-1270., 2000.
85. Ikeda, N., Miyoshi, Y., Yoneda, K., Shiba, E., Sekihara, Y., Kinoshita, M., and Noguchi, S. Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. Int J Cancer, 91: 83-88., 2001.
86. Esteller, M., Silva, J. M., Dominguez, G., Bonilla, F., Matias-Guiu, X., Lerma, E., Bussaglia, E., Prat, J., Harkes, I. C., Repasky, E. A., Gabrielson, E., Schutte, M., Baylin, S. B., and Herman, J. G. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst, 92: 564-569., 2000.
87. Rice, J. C., Massey-Brown, K. S., and Futscher, B. W. Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Oncogene, 17: 1807-1812., 1998.
88. Chan, K. Y., Ozcelik, H., Cheung, A. N., Ngan, H. Y., and Khoo, U. S. Epigenetic factors controlling the BRCA1 and BRCA2 genes in sporadic ovarian cancer. Cancer Res, 62: 4151-4156., 2002.
89. Rice, J. C., Ozcelik, H., Maxeiner, P., Andrulis, I., and Futscher, B. W. Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis, 21: 1761-1765., 2000.
90. Magdinier, F., Ribieras, S., Lenoir, G. M., Frappart, L., and Dante, R. Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region. Oncogene, 17: 3169-3176., 1998.
91. Niwa, Y., Oyama, T., and Nakajima, T. BRCA1 expression status in relation to DNA methylation of the BRCA1 promoter region in sporadic breast cancers. Jpn J Cancer Res, 91: 519-526., 2000.
92. Miyamoto, K., Fukutomi, T., Asada, K., Wakazono, K., Tsuda, H., Asahara, T., Sugimura, T., and Ushijima, T. Promoter hypermethylation and post-transcriptional mechanisms for reduced BRCA1 immunoreactivity in sporadic human breast cancers. Jpn J Clin Oncol, 32: 79-84., 2002.
93. Bianco, T., Chenevix-Trench, G., Walsh, D. C., Cooper, J. E., and Dobrovic, A. Tumour-specific distribution of BRCA1 promoter region methylation supports a pathogenetic role in breast and ovarian cancer. Carcinogenesis, 21: 147-151., 2000.
94. Lo, Y. L., Yu, J. C., Huang, C. S., Tseng, S. L., Chang, T. M., Chang, K. J., Wu, C. W., and Shen, C. Y. Allelic loss of the BRCA1 and BRCA2 genes and other regions on 17q and 13q in breast cancer among women from Taiwan (area of low incidence but early onset). Int J Cancer, 79: 580-587., 1998.
95. Bieche, I., Nogues, C., and Lidereau, R. Overexpression of BRCA2 gene in sporadic breast tumours. Oncogene, 18: 5232-5238., 1999.
96. Ottini, L., Masala, G., D'Amico, C., Mancini, B., Saieva, C., Aceto, G., Gestri, D., Vezzosi, V., Falchetti, M., De Marco, M., Paglierani, M., Cama, A., Bianchi, S., Mariani-Costantini, R., and Palli, D. BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res, 63: 342-347., 2003.
97. Claes, K., Vandesompele, J., Poppe, B., Dahan, K., Coene, I., De Paepe, A., and Messiaen, L. Pathological splice mutations outside the invariant AG/GT splice sites of BRCA1 exon 5 increase alternative transcript levels in the 5' end of the BRCA1 gene. Oncogene, 21: 4171-4175., 2002.
98. Bieche, I. and Lidereau, R. Increased level of exon 12 alternatively spliced BRCA2 transcripts in tumor breast tissue compared with normal tissue. Cancer Res, 59: 2546-2550., 1999.
99. Baldwin, R. L., Nemeth, E., Tran, H., Shvartsman, H., Cass, I., Narod, S., and Karlan, B. Y. BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res, 60: 5329-5333., 2000.
100. Takebayashi, Y., Nakayama, K., Kanzaki, A., Miyashita, H., Ogura, O., Mori, S., Mutoh, M., Miyazaki, K., Fukumoto, M., and Pommier, Y. Loss of heterozygosity of nucleotide excision repair factors in sporadic ovarian, colon and lung carcinomas: implication for their roles of carcinogenesis in human solid tumors. Cancer Lett, 174: 115-125., 2001.
101. Gras, E., Cortes, J., Diez, O., Alonso, C., Matias-Guiu, X., Baiget, M., and Prat, J. Loss of heterozygosity on chromosome 13q12-q14, BRCA-2 mutations and lack of BRCA-2 promoter hypermethylation in sporadic epithelial ovarian tumors. Cancer, 92: 787-795., 2001.
102. Hilton, J. L., Geisler, J. P., Rathe, J. A., Hattermann-Zogg, M. A., DeYoung, B., and Buller, R. E. Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst, 94: 1396-1406., 2002.
103. Su, J. and Ciftci, K. Changes in BRCA1 and BRCA2 expression produced by chemotherapeutic agents in human breast cancer cells. Int J Biochem Cell Biol, 34: 950-957., 2002.
104. Edwards, S. M., Dunsmuir, W. D., Gillett, C. E., Lakhani, S. R., Corbishley, C., Young, M., Kirby, R. S., Dearnaley, D. P., Dowe, A., Ardern-Jones, A., Kelly, J., Spurr, N., Barnes, D. M., and Eeles, R. A. Immunohistochemical expression of BRCA2 protein and allelic loss at the BRCA2 locus in prostate cancer. CRC/BPG UK Familial Prostate Cancer Study Collaborators. Int J Cancer, 78: 1-7., 1998.
105. Gayther, S. A., de Foy, K. A., Harrington, P., Pharoah, P., Dunsmuir, W. D., Edwards, S. M., Gillett, C., Ardern-Jones, A., Dearnaley, D. P., Easton, D. F., Ford, D., Shearer, R. J., Kirby, R. S., Dowe, A. L., Kelly, J., Stratton, M. R., Ponder, B. A., Barnes, D., and Eeles, R. A. The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res, 60: 4513-4518., 2000.
106. Garcia, J. M., Rodriguez, R., Dominguez, G., Silva, J. M., Provencio, M., Silva, J., Colmenarejo, A., Millan, I., Munoz, C., Salas, C., Coca, S., Espana, P., and Bonilla, F. Prognostic significance of the allelic loss of the BRCA1 gene in colorectal cancer. Gut, 52: 1756-1763., 2003.
107. Jakubowska, A., Huzarski, T., Lubinski, J., Nej, K., and Scott, R. J. BRCA2 gene mutations in families with aggregations of breast and stomach cancers. Br J Cancer, 87: 888-891., 2002.
108. Schutte, M., da Costa, L. T., Hahn, S. A., Moskaluk, C., Hoque, A. T., Rozenblum, E., Weinstein, C. L., Bittner, M., Meltzer, P. S., Trent, J. M., and et al. Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region. Proc Natl Acad Sci U S A, 92: 5950-5954., 1995.
109. Gorgoulis, V. G., Kotsinas, A., Zacharatos, P., Mariatos, G., Liloglou, T., Tsoli, E., Kokotas, S., Fassoulas, C., Field, J. K., and Kittas, C. Association of allelic imbalance at locus D13S171 (BRCA2) and p53 alterations with tumor kinetics and chromosomal instability (aneuploidy) in nonsmall cell lung carcinoma. Cancer, 89: 1933, 2000.
110. Boettger, M. B., Sergi, C., and Meyer, P. BRCA1/2 mutation screening and LOH analysis of lung adenocarcinoma tissue in a multiple-cancer patient with a strong family history of breast cancer. J Carcinog, 2: 5., 2003.
111. Marsit, C. J., Liu, M., Nelson, H. H., Posner, M., Suzuki, M., and Kelsey, K. T. Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. Oncogene, 23: 1000-1004., 2004.
112. Lim, D. S., Vogel, H., Willerford, D. M., Sands, A. T., Platt, K. A., and Hasty, P. Analysis of ku80-mutant mice and cells with deficient levels of p53. Mol Cell Biol, 20: 3772-3780., 2000.
113. Hironaka, K., Factor, V. M., Calvisi, D. F., Conner, E. A., and Thorgeirsson, S. S. Dysregulation of DNA repair pathways in a transforming growth factor alpha/c-myc transgenic mouse model of accelerated hepatocarcinogenesis. Lab Invest, 83: 643-654., 2003.
114. Tong, W. M., Cortes, U., Hande, M. P., Ohgaki, H., Cavalli, L. R., Lansdorp, P. M., Haddad, B. R., and Wang, Z. Q. Synergistic role of Ku80 and poly(ADP-ribose) polymerase in suppressing chromosomal aberrations and liver cancer formation. Cancer Res, 62: 6990-6996., 2002.
115. Korabiowska, M., Bauer, H., Quentin, T., Stachura, J., Cordon-Cardo, C., and Brinck, U. Application of new in situ hybridization probes for Ku70 and Ku80 in tissue microarrays of paraffin-embedded malignant melanomas: correlation with immunohistochemical analysis. Hum Pathol, 35: 210-216., 2004.
116. Korabiowska, M., Tscherny, M., Stachura, J., Berger, H., Cordon-Cardo, C., and Brinck, U. Differential expression of DNA nonhomologous end-joining proteins Ku70 and Ku80 in melanoma progression. Mod Pathol, 15: 426-433., 2002.
117. Korabiowska, M., Tscherny, M., Grohmann, U., Honig, J. F., Bartkowski, S. B., Cordon-Cardo, C., and Brinck, U. Decreased expression of Ku70/Ku80 proteins in malignant melanomas of the oral cavity. Anticancer Res, 22: 193-196., 2002.
118. Friesland, S., Kanter-Lewensohn, L., Tell, R., Munck-Wikland, E., Lewensohn, R., and Nilsson, A. Expression of Ku86 confers favorable outcome of tonsillar carcinoma treated with radiotherapy. Head Neck, 25: 313-321., 2003.
119. Harima, Y., Sawada, S., Miyazaki, Y., Kin, K., Ishihara, H., Imamura, M., Sougawa, M., Shikata, N., and Ohnishi, T. Expression of Ku80 in cervical cancer correlates with response to radiotherapy and survival. Am J Clin Oncol, 26: e80-85., 2003.
120. Rigas, B., Borgo, S., Elhosseiny, A., Balatsos, V., Manika, Z., Shinya, H., Kurihara, N., Go, M., and Lipkin, M. Decreased expression of DNA-dependent protein kinase, a DNA repair protein, during human colon carcinogenesis. Cancer Res, 61: 8381-8384., 2001.
121. Lim, J. W., Kim, H., and Kim, K. H. Expression of Ku70 and Ku80 mediated by NF-kappa B and cyclooxygenase-2 is related to proliferation of human gastric cancer cells. J Biol Chem, 277: 46093-46100. Epub 42002 Sep 46024., 2002.
122. Cho, N. H., Cordon-Cardo, C., Li, G. C., and Kim, S. H. Allotype imbalance or microsatellite mutation in low-grade soft tissue sarcomas of the extremities in adults. J Pathol, 198: 21-29., 2002.
123. Pucci, S., Mazzarelli, P., Rabitti, C., Giai, M., Gallucci, M., Flammia, G., Alcini, A., Altomare, V., and Fazio, V. M. Tumor specific modulation of KU70/80 DNA binding activity in breast and bladder human tumor biopsies. Oncogene, 20: 739-747., 2001.
124. Kinzler, K. W. and Vogelstein, B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature, 386: 761, 763., 1997.
125. Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B., and Craig, R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res, 51: 6304-6311., 1991.
126. Lane, D. P. Cancer. p53, guardian of the genome. Nature, 358: 15-16., 1992.
127. Amare Kadam, P. S., Ghule, P., Jose, J., Bamne, M., Kurkure, P., Banavali, S., Sarin, R., and Advani, S. Constitutional genomic instability, chromosome aberrations in tumor cells and retinoblastoma. Cancer Genet Cytogenet, 150: 33-43., 2004.
128. Srivastava, S., Zou, Z. Q., Pirollo, K., Blattner, W., and Chang, E. H. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature, 348: 747-749., 1990.
129. Wang, J. Y., Hsieh, J. S., Chang, M. Y., Huang, T. J., Chen, F. M., Cheng, T. L., Alexandersen, K., Huang, Y. S., Tzou, W. S., and Lin, S. R. Molecular Detection of APC, K- ras, and p53 Mutations in the Serum of Colorectal Cancer Patients as Circulating Biomarkers.
130. Moll, U., Lau, R., Sypes, M. A., Gupta, M. M., and Anderson, C. W. DNA-PK, the DNA-activated protein kinase, is differentially expressed in normal and malignant human tissues. Oncogene, 18: 3114-3126., 1999.
131. Broll, R., Stark, A., Windhovel, U., Best, R., Strik, M. W., Schimmelpenning, H., Schwandner, O., Kujath, P., Bruch, H. P., and Duchrow, M. Expression of p53 and mdm2 mRNA and protein in colorectal carcinomas. Eur J Cancer, 35: 1083-1088., 1999.
132. Ko, J. L., Cheng, Y. W., Chang, S. L., Su, J. M., Chen, C. Y., and Lee, H. MDM2 mRNA expression is a favorable prognostic factor in non-small-cell lung cancer. Int J Cancer, 89: 265-270., 2000.
133. Pinyol, M., Hernandez, L., Martinez, A., Cobo, F., Hernandez, S., Bea, S., Lopez-Guillermo, A., Nayach, I., Palacin, A., Nadal, A., Fernandez, P. L., Montserrat, E., Cardesa, A., and Campo, E. INK4a/ARF locus alterations in human non-Hodgkin's lymphomas mainly occur in tumors with wild-type p53 gene. Am J Pathol, 156: 1987-1996., 2000.
134. Bombardieri, E., Seregni, E., Daidone, M. G., Benini, E., Massaron, S., Ferrari, L., Di Fronzo, G., and Silvestrini, R. P53 accumulation in primary breast cancer: a comparison between immunohistochemistry and a novel luminometric immunoassay. Tumour Biol., 19: 12-18., 1998.
135. Yang, S., Wang, M., and You, W. Overexpression of c-myc and p53 gene in human hepato-cellular carcinoma--a study with immunohistochemistry and in situ hybridization. Zhonghua Zhong Liu Za Zhi, 17: 415-417., 1995.
136. Shiao, Y. H., Palli, D., Caporaso, N. E., Alvord, W. G., Amorosi, A., Nesi, G., Saieva, C., Masala, G., Fraumeni, J. F., Jr., and Rice, J. M. Genetic and immunohistochemical analyses of p53 independently predict regional metastasis of gastric cancers. Cancer Epidemiol Biomarkers Prev, 9: 631-633., 2000.
137. Wu, M. S., Shun, C. T., Sheu, J. C., Wang, H. P., Wang, J. T., Lee, W. J., Chen, C. J., Wang, T. H., and Lin, J. T. Overexpression of mutant p53 and c-erbB-2 proteins and mutations of the p15 and p16 genes in human gastric carcinoma: with respect to histological subtypes and stages. J Gastroenterol Hepatol, 13: 305-310., 1998.
138. Pindzola, J. A., Kovatich, A. J., and Bibbo, M. p53 immunohistochemistry for distinguishing reactive mesothelium from low grade ovarian carcinoma. Acta Cytol, 44: 31-36., 2000.
139. Chino, O., Kijima, H., Shimada, H., Nishi, T., Tanaka, H., Kise, Y., Kenmochi, T., Himeno, S., Machimura, T., Tanaka, M., Inokuchi, S., Tajima, T., Osamura, R. Y., and Makuuchi, H. Accumulation of p53 in esophageal squamous cell carcinoma. Int J Mol Med, 8: 359-363., 2001.
140. Koga, T., Hashimoto, S., Sugio, K., Yoshino, I., Nakagawa, K., Yonemitsu, Y., Sugimachi, K., and Sueishi, K. Heterogeneous distribution of P53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with P53 gene mutation. Int J Cancer, 95: 232-239., 2001.
141. Geck, P., Sonnenschein, C., and Soto, A. M. The D13S171 marker, misannotated to BRCA2, links the AS3 gene to various cancers. Am J Hum Genet, 69: 461-463., 2001.
142. Wilson, C. A., Payton, M. N., Elliott, G. S., Buaas, F. W., Cajulis, E. E., Grosshans, D., Ramos, L., Reese, D. M., Slamon, D. J., and Calzone, F. J. Differential subcellular localization, expression and biological toxicity of BRCA1 and the splice variant BRCA1-delta11b. Oncogene, 14: 1-16., 1997.
143. Thakur, S., Zhang, H. B., Peng, Y., Le, H., Carroll, B., Ward, T., Yao, J., Farid, L. M., Couch, F. J., Wilson, R. B., and Weber, B. L. Localization of BRCA1 and a splice variant identifies the nuclear localization signal. Mol Cell Biol, 17: 444-452., 1997.
144. Xu, C. F., Chambers, J. A., Nicolai, H., Brown, M. A., Hujeirat, Y., Mohammed, S., Hodgson, S., Kelsell, D. P., Spurr, N. K., Bishop, D. T., and Solomon, E. Mutations and alternative splicing of the BRCA1 gene in UK breast/ovarian cancer families. Genes Chromosomes Cancer, 18: 102-110., 1997.
145. Orban, T. I. and Olah, E. Emerging roles of BRCA1 alternative splicing. Mol Pathol, 56: 191-197., 2003.
146. Fackenthal, J. D., Cartegni, L., Krainer, A. R., and Olopade, O. I. BRCA2 T2722R is a deleterious allele that causes exon skipping. Am J Hum Genet, 71: 625-631. Epub 2002 Jul 2019., 2002.
147. Speevak, M. D., Young, S. S., Feilotter, H., and Ainsworth, P. Alternatively spliced, truncated human BRCA2 isoforms contain a novel coding exon. Eur J Hum Genet, 11: 951-954., 2003.
148. Hofmann, W., Horn, D., Huttner, C., Classen, E., and Scherneck, S. The BRCA2 variant 8204G>A is a splicing mutation and results in an in frame deletion of the gene. J Med Genet, 40: e23., 2003.
149. Bernard-Gallon, D. J., Dechelotte, P., Rio, P. G., and Bignon, Y. J. Expression of human BRCA1 and BRCA2 proteins in lung from a fetus at 19 weeks' gestation. Int J Cancer, 82: 771-773., 1999.
150. Bernard-Gallon, D. J., Dechelotte, P., Vissac, C., Aunoble, B., Cravello, L., Malpuech, G., and Bignon, Y. J. BRCA1 and BRCA2 protein expressions in an ovotestis of a 46, XX true hermaphrodite. Breast Cancer Res., 3: 61-65, 2000.
151. Bogdani, M., Teugels, E., De Greve, J., Bourgain, C., Neyns, B., and Pipeleers-Marichal, M. Loss of nuclear BRCA1 localization in breast carcinoma is age dependent. Virchows Arch, 440: 274-279., 2002.
152. Bernard-Gallon, D., Peffault De Latour, M., Rio, P., Favy, D., Hizel, C., Vissac, C., and Bignon, Y. J. BRCA2 protein expression in sporadic breast carcinoma with or without allelic loss of BRCA2. Int J Cancer, 86: 453-456., 2000.
153. Mimori, T., Ohosone, Y., Hama, N., Suwa, A., Akizuki, M., Homma, M., Griffith, A. J., and Hardin, J. A. Isolation and characterization of cDNA encoding the 80-kDa subunit protein of the human autoantigen Ku (p70/p80) recognized by autoantibodies from patients with scleroderma-polymyositis overlap syndrome. Proc Natl Acad Sci U S A, 87: 1777-1781., 1990.
154. Li, B. and Comai, L. Functional interaction between Ku and the werner syndrome protein in DNA end processing. J Biol Chem, 275: 28349-28352., 2000.
155. Li, B. and Comai, L. Requirements for the nucleolytic processing of DNA ends by the Werner syndrome protein-Ku70/80 complex. J Biol Chem, 276: 9896-9902., 2001.
156. Cheung, A. M., Elia, A., Tsao, M. S., Done, S., Wagner, K. U., Hennighausen, L., Hakem, R., and Mak, T. W. Brca2 deficiency does not impair mammary epithelium development but promotes mammary adenocarcinoma formation in p53(+/-) mutant mice. Cancer Res, 64: 1959-1965., 2004.
157. Gasco, M., Yulug, I. G., and Crook, T. TP53 mutations in familial breast cancer: functional aspects. Hum Mutat, 21: 301-306., 2003.
158. Reedy, M. B., Hang, T., Gallion, H., Arnold, S., and Smith, S. A. Antisense inhibition of BRCA1 expression and molecular analysis of hereditary tumors indicate that functional inactivation of the p53 DNA damage response pathway is required for BRCA-associated tumorigenesis. Gynecol Oncol, 81: 441-446., 2001.
159. Wu, K., Jiang, S. W., and Couch, F. J. p53 mediates repression of the BRCA2 promoter and down-regulation of BRCA2 mRNA and protein levels in response to DNA damage. J Biol Chem, 278: 15652-15660., 2003.
160. Welcsh, P. L., Owens, K. N., and King, M. C. Insights into the functions of BRCA1 and BRCA2. Trends Genet, 16: 69-74., 2000.
161. Sensi, E., Tancredi, M., Aretini, P., Cipollini, G., Naccarato, A. G., Viacava, P., Bevilacqua, G., and Caligo, M. A. p53 inactivation is a rare event in familial breast tumors negative for BRCA1 and BRCA2 mutations. Breast Cancer Res Treat, 82: 1-9., 2003.
162. Tseng, S. L., Yu, I. C., Yue, C. T., Chang, S. F., Chang, T. M., Wu, C. W., and Shen, C. Y. Allelic loss at BRCA1, BRCA2, and adjacent loci in relation to TP53 abnormality in breast cancer. Genes Chromosomes Cancer, 20: 377-382., 1997.
163. Katsama, A., Sourvinos, G., Zachos, G., and Spandidos, D. A. Allelic loss at the BRCA1, BRCA2 and TP53 loci in human sporadic breast carcinoma. Cancer Lett, 150: 165-170., 2000.
164. Santos, S. C., Cavalli, L. R., Cavalli, I. J., Lima, R. S., Haddad, B. R., and Ribeiro, E. M. Loss of heterozygosity of the BRCA1 and FHIT genes in patients with sporadic breast cancer from Southern Brazil. J Clin Pathol, 57: 374-377., 2004.
165. Kirchhoff, T., Kauff, N. D., Mitra, N., Nafa, K., Huang, H., Palmer, C., Gulati, T., Wadsworth, E., Donat, S., Robson, M. E., Ellis, N. A., and Offit, K. BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res, 10: 2918-2921., 2004.
166. Kwiatkowska, E., Brozek, I., Izycka-Swieszewska, E., Limon, J., and Mackiewicz, A. Novel BRCA2 mutation in a Polish family with hamartoma and two male breast cancers. J Med Genet, 39: E35., 2002.
167. Forsti, A., Luo, L., Vorechovsky, I., Soderberg, M., Lichtenstein, P., and Hemminki, K. Allelic imbalance on chromosomes 13 and 17 and mutation analysis of BRCA1 and BRCA2 genes in monozygotic twins concordant for breast cancer. Carcinogenesis, 22: 27-33., 2001.
168. Egawa, C., Miyoshi, Y., Taguchi, T., Tamaki, Y., and Noguchi, S. High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients. Int J Cancer, 98: 879-882., 2002.
169. El-Tamer, M., Russo, D., Troxel, A., Bernardino, L. P., Mazziotta, R., Estabrook, A., Ditkoff, B. A., Schnabel, F., and Mansukhani, M. Survival and recurrence after breast cancer in BRCA1/2 mutation carriers. Ann Surg Oncol, 11: 157-164., 2004.
170. Otis, C. N., Krebs, P. A., Albuquerque, A., Quezado, M. M., San Juan, X., Sobel, M. E., and Merino, M. J. Loss of heterozygosity of p53, BRCA1, VHL, and estrogen receptor genes in breast carcinoma: correlation with related protein products and morphologic features. Int J Surg Pathol, 10: 237-245., 2002.
171. Lee, W. Y. Frequent loss of BRCA1 nuclear expression in young women with breast cancer: an immunohistochemical study from an area of low incidence but early onset. Appl Immunohistochem Mol Morphol, 10: 310-315., 2002.
172. Malander, S., Ridderheim, M., Masback, A., Loman, N., Kristoffersson, U., Olsson, H., Nilbert, M., and Borg, A. One in 10 ovarian cancer patients carry germ line BRCA1 or BRCA2 mutations: results of a prospective study in Southern Sweden. Eur J Cancer, 40: 422-428., 2004.
173. Satagopan, J. M., Boyd, J., Kauff, N. D., Robson, M., Scheuer, L., Narod, S., and Offit, K. Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res, 8: 3776-3781., 2002.