DNA repair: The link between primary immunodeficiency and cancer

Annals of the New York Academy of Sciences

Volumn 1246, Issue 1, 2011, Pages 50-63

  de Miranda, Noel F C C ^a   Björkman, Andrea ^a   Pan Hammarström, Qiang ^a  

^a KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

Cancer; Class switch recombination; DNA repair; Genomic instability; Primary immunodeficiency; V(D)J recombination

Indexed keywords

ADAPTIVE IMMUNITY; CANCER RISK; CANCER SUSCEPTIBILITY; CARCINOGENESIS; DNA DAMAGE; DNA REPAIR; GENE REARRANGEMENT; GENETIC RECOMBINATION; GENOMIC INSTABILITY; HUMAN; IMMUNE DEFICIENCY; IMMUNE SYSTEM; LYMPHOID ORGAN; LYMPHOMA; NONHUMAN; REVIEW; SOMATIC HYPERMUTATION; TUMOR IMMUNITY;

EID: 84855321819     PISSN: 00778923     EISSN: 17496632     Source Type: Book Series    
DOI: 10.1111/j.1749-6632.2011.06322.x     Document Type: Review

References (157)

1. Zimmer, C. 2009. Origins. On the origin of sexual reproduction. Science 324: 1254-1256.
2. Caporale, L.H. 2000. Mutation is modulated: implications for evolution. Bioessays 22: 388-395.
3. Radman, M., I. Matic & F. Taddei. 1999. Evolution of evolvability. Ann. N. Y. Acad. Sci. 870: 146-155.
4. Howard, J.C. 1991. Immunology. Disease and evolution. Nature 352: 565-567.
5. Bonilla, F.A. & H.C. Oettgen. 2010. Adaptive immunity. J. Allergy Clin. Immunol. 125: S33-S40.
6. Revy, P., D. Buck, D.F. Le & J.P. de Villartay. 2005. The repair of DNA damages/modifications during the maturation of the immune system: lessons from human primary immunodeficiency disorders and animal models. Adv. Immunol. 87: 237-295.
7. Moses, R.E. 2001. DNA damage processing defects and disease. Annu. Rev. Genomics Hum. Genet. 2: 41-68.
8. Puebla-Osorio, N. & C. Zhu. 2008. DNA damage and repair during lymphoid development: antigen receptor diversity, genomic integrity and lymphomagenesis. Immunol. Res. 41: 103-122.
9. Slatter, M.A. & A.R. Gennery. 2010. Primary immunodeficiency syndromes. Adv. Exp. Med. Biol. 685: 146-165.
10. Chistiakov, D.A., N.V. Voronova & P.A. Chistiakov. 2008. Genetic variations in DNA repair genes, radiosensitivity to cancer and susceptibility to acute tissue reactions in radiotherapy-treated cancer patients. Acta Oncol. 47: 809-824.
11. Nahas, S.A. & R.A. Gatti. 2009. DNA double strand break repair defects, primary immunodeficiency disorders, and 'radiosensitivity'. Curr. Opin. Allergy Clin. Immunol. 9: 510-516.
12. Lieber, M.R., C.P. Chang, M. Gallo, et al. 1994. The mechanism of V(D)J recombination: site-specificity, reaction fidelity and immunologic diversity. Semin. Immunol. 6: 143-153.
13. Stavnezer, J., J.E. Guikema & C.E. Schrader. 2008. Mechanism and regulation of class switch recombination. Annu. Rev. Immunol. 26: 261-292.
14. Peled, J.U., F.L. Kuang, M.D. Iglesias-Ussel, et al. 2008. The biochemistry of somatic hypermutation. Annu. Rev. Immunol. 26: 481-511.
15. Oettinger, M.A., D.G. Schatz, C. Gorka & D. Baltimore. 1990. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248: 1517-1523.
16. Schatz, D.G., M.A. Oettinger & D. Baltimore. 1989. The V(D)J recombination activating gene, RAG-1. Cell 59: 1035-1048.
17. Lieber, M.R. 2010. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem. 79: 181-211.
18. Muramatsu, M., K. Kinoshita, S. Fagarasan, et al. 2000. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102: 553-563.
19. Stavnezer, J., A. Bjorkman, L. Du, et al. 2010. Mapping of switch recombination junctions, a tool for studying DNA repair pathways during immunoglobulin class switching. Adv. Immunol. 108: 45-109.
20. Kotnis, A., L. Du, C. Liu, et al. 2009. Non-homologous end joining in class switch recombination: the beginning of the end. Philos. Trans. R. Soc. Lond B Biol. Sci. 364: 653-665.
21. Zhang, Y., M. Gostissa, D.G. Hildebrand, et al. 2010. The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers. Adv. Immunol. 106: 93-133.
22. Boboila, C., C. Yan, D.R. Wesemann, et al. 2010. Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. J. Exp. Med. 207: 417-427.
23. Du, L., M. van der Burg, S.W. Popov, et al. 2008. Involvement of Artemis in nonhomologous end-joining during immunoglobulin class switch recombination. J. Exp. Med. 205: 3031-3040.
24. Pan-Hammarstrom, Q., A.M. Jones, A. Lahdesmaki, et al. 2005. Impact of DNA ligase IV on nonhomologous end joining pathways during class switch recombination in human cells. J. Exp. Med. 201: 189-194.
25. Yan, C.T., C. Boboila, E.K. Souza, et al. 2007. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449: 478-482.
26. Corneo, B., R.L. Wendland, L. Deriano, et al. 2007. Rag mutations reveal robust alternative end joining. Nature 449: 483-486.
27. Du, L., D.K. Dunn-Walters, K.H. Chrzanowska, et al. 2008. A regulatory role for NBS1 in strand-specific mutagenesis during somatic hypermutation. PLoS One 3: e2482.
28. Niehues, T., R. Perez-Becker & C. Schuetz. 2010. More than just SCID-the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin. Immunol. 135: 183-192.
29. Schwarz, K., G.H. Gauss, L. Ludwig, et al. 1996. RAG mutations in human B cell-negative SCID. Science 274: 97-99.
30. Moshous, D., I. Callebaut, C.R. De, et al. 2001. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105: 177-186.
31. Noordzij, J.G., N.M. Wulffraat, A. Haraldsson, et al. 2009. Ataxia-telangiectasia patients presenting with hyper-IgM syndrome. Arch. Dis. Child. 94: 448-449.
32. Nowak-Wegrzyn, A., T.O. Crawford, J.A. Winkelstein, et al. 2004. Immunodeficiency and infections in ataxia-telangiectasia. J. Pediatr. 144: 505-511.
33. Staples, E.R., E.M. McDermott, A. Reiman, et al. 2008. Immunodeficiency in ataxia telangiectasia is correlated strongly with the presence of two null mutations in the ataxia telangiectasia mutated gene. Clin. Exp. Immunol. 153: 214-220.
34. Peterson, R.D., J.D. Funkhouser, C.M. Tuck-Muller & R.A. Gatti. 1992. Cancer susceptibility in ataxia-telangiectasia. Leukemia 6 (Suppl. 1): 8-13.
35. Taylor, A.M., J.A. Metcalfe, J. Thick & Y.F. Mak. 1996. Leukemia and lymphoma in ataxia telangiectasia. Blood 87: 423-438.
36. van Engelen, B.G., J.A. Hiel, F.J. Gabreels, et al. 2001. Decreased immunoglobulin class switching in Nijmegen Breakage syndrome due to the DNA repair defect. Hum. Immunol. 62: 1324-1327.
37. Gregorek, H., K.H. Chrzanowska, J. Michalkiewicz, et al. 2002. Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: an 8-year follow-up study in a single centre. Clin. Exp. Immunol. 130: 319-324.
38. Demuth, I. & M. Digweed. 2007. The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by Nijmegen breakage syndrome. Oncogene 26: 7792-7798.
39. The International Nijmegen Breakage Syndrome Study Group. 2000. Nijmegen breakage syndrome. Arch. Dis. Child. 82: 400-406.
40. Gladkowska-Dura, M., K. Dzierzanowska-Fangrat, W.T. Dura, et al. 2008. Unique morphological spectrum of lymphomas in Nijmegen breakage syndrome (NBS) patients with high frequency of consecutive lymphoma formation. J. Pathol. 216: 337-344.
41. Noordzij, J.G., N.S. Verkaik, M. van der Burg, et al. 2003. Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow. Blood 101: 1446-1452.
42. Moshous, D., C. Pannetier, R.R. Chasseval, et al. 2003. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J. Clin. Invest. 111: 381-387.
43. Ijspeert, H., A.C. Lankester, J.M. van den Berg, et al. 2011. Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide. Genes Immun. 12: 434-444.
44. Ege, M., Y. Ma, B. Manfras, et al. 2005. Omenn syndrome due to ARTEMIS mutations. Blood 105: 4179-4186.
45. Buck, D., D. Moshous, C.R. De, et al. 2006. Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. Eur. J. Immunol. 36: 224-235.
46. van der Burg, M., L.R. van Veelen, N.S. Verkaik, et al. 2006. A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. J. Clin. Invest. 116: 137-145.
47. O'Driscoll, M., K.M. Cerosaletti, P.M. Girard, et al. 2001. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol. Cell 8: 1175-1185.
48. Grunebaum, E., A. Bates & C.M. Roifman. 2008. Omenn syndrome is associated with mutations in DNA ligase IV. J. Allergy Clin. Immunol. 122: 1219-1220.
49. Enders, A., P. Fisch, K. Schwarz, et al. 2006. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J. Immunol. 176: 5060-5068.
50. Toita, N., N. Hatano, S. Ono, et al. 2007. Epstein-Barr virus-associated B-cell lymphoma in a patient with DNA ligase IV (LIG4) syndrome. Am. J. Med. Genet. A. 143: 742-745.
51. Riballo, E., S.E. Critchlow, S.H. Teo, et al. 1999. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr. Biol. 9: 699-702.
52. Ben-Omran, T.I., K. Cerosaletti, P. Concannon, et al. 2005. A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am. J. Med. Genet. A. 137A: 283-287.
53. Webster, A.D., D.E. Barnes, C.F. Arlett, et al. 1992. Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene. Lancet 339: 1508-1509.
54. Kondo, N., F. Motoyoshi, S. Mori, et al. 1992. Long-term study of the immunodeficiency of Bloom's syndrome. Acta Paediatr. 81: 86-90.
55. Van Kerckhove, C.W., J.L. Ceuppens, M. Vanderschueren-Lodeweyckx, et al. 1988. Bloom's syndrome. Clinical features and immunologic abnormalities of four patients. Am. J. Dis. Child. 142: 1089-1093.
56. Etzioni, A., N. Lahat, A. Benderly, et al. 1989. Humoral and cellular immune dysfunction in a patient with Bloom's syndrome and recurrent infections. J. Clin. Lab Immunol. 28: 151-154.
57. German, J. 1997. Bloom's syndrome. XX. The first 100 cancers. Cancer Genet. Cytogenet. 93: 100-106.
58. Auerbach, A.D. 2009. Fanconi anemia and its diagnosis. Mutat. Res. 668: 4-10.
59. Peron, S., A. Metin, P. Gardes, et al. 2008. Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J. Exp. Med. 205: 2465-2472.
60. Ostergaard, J.R., L. Sunde & H. Okkels. 2005. Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6. Am. J. Med. Genet. A. 139A: 96-105.
61. Whiteside, D., R. McLeod, G. Graham, et al. 2002. A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. Cancer Res. 62: 359-362.
62. Offer, S.M., Q. Pan-Hammarstrom, L. Hammarstrom & R.S. Harris. 2010. Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID. PLoS One 5: e12260.
63. Scott, R.H., S. Mansour, K. Pritchard-Jones, et al. 2007. Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nat. Clin. Pract. Oncol. 4: 130-134.
64. Wimmer, K. & J. Etzler. 2008. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum. Genet. 124: 105-122.
65. van der Burg, M., H. Ijspeert, N.S. Verkaik, et al. 2009. A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. J. Clin. Invest. 119: 91-98.
66. Buck, D., L. Malivert, C.R. De, et al. 2006. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124: 287-299.
67. Cagdas, D., T.T. Ozgur, G.T. Asal, et al. 2011. Two SCID cases with Cernunnos-XLF deficiency successfully treated by hematopoietic stem cell transplantation. Pediatr. Transplant. 2011 Apr 27. doi:. [Epub ahead of print].
68. Faraci, M., E. Lanino, C. Micalizzi, et al. 2009. Unrelated hematopoietic stem cell transplantation for Cernunnos-XLF deficiency. Pediatr. Transplant. 13: 785-789.
69. Turul, T., I. Tezcan & O. Sanal. 2011. Cernunnos deficiency: a case report. J. Investig. Allergol. Clin. Immunol. 21: 313-316.
70. Pan-Hammarstrom, Q. & L. Hammarstrom. 2008. Antibody deficiency diseases. Eur. J. Immunol. 38: 327-333.
71. Durandy, A., N. Taubenheim, S. Peron & A. Fischer. 2007. Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies. Adv. Immunol. 94: 275-306.
72. Revy, P., T. Muto, Y. Levy, et al. 2000. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102: 565-575.
73. Imai, K., G. Slupphaug, W.I. Lee, et al. 2003. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat. Immunol. 4: 1023-1028.
74. Sekine, H., R.C. Ferreira, Q. Pan-Hammarstrom, et al. 2007. Role for Msh5 in the regulation of Ig class switch recombination. Proc. Natl. Acad. Sci. USA 104: 7193-7198.
75. Stewart, G.S., T. Stankovic, P.J. Byrd, et al. 2007. RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling. Proc. Natl. Acad. Sci. USA 104: 16910-16915.
76. Stewart, G.S., S. Panier, K. Townsend, et al. 2009. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136: 420-434.
77. Devgan, S.S., O. Sanal, C. Doil, et al. 2011. Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia. Cell Death Differ. 18: 1500-1506.
78. Lahdesmaki, A., A.M. Taylor, K.H. Chrzanowska & Q. Pan-Hammarstrom. 2004. Delineation of the role of the Mre11 complex in class switch recombination. J. Biol. Chem. 279: 16479-16487.
79. Ellis, N.A., J. Groden, T.Z. Ye, et al. 1995. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83: 655-666.
80. Babbe, H., J. McMenamin, E. Hobeika, et al. 2009. Genomic instability resulting from Blm deficiency compromises development, maintenance, and function of the B cell lineage. J. Immunol. 182: 347-360.
81. Kitao, H. & M. Takata. 2011. Fanconi anemia: a disorder defective in the DNA damage response. Int. J. Hematol. 93: 417-424.
82. Krijger, P.H., N. Wit, P.C. van den Berk & H. Jacobs. 2010. The Fanconi anemia core complex is dispensable during somatic hypermutation and class switch recombination. PLoS One 5: e15236.
83. Li, Z., D.I. Dordai, J. Lee & S. Desiderio. 1996. A conserved degradation signal regulates RAG-2 accumulation during cell division and links V(D)J recombination to the cell cycle. Immunity 5: 575-589.
84. Lin, W.C. & S. Desiderio. 1994. Cell cycle regulation of V(D)J recombination-activating protein RAG-2. Proc. Natl. Acad. Sci. USA 91: 2733-2737.
85. Rush, J.S., M. Liu, V.H. Odegard, et al. 2005. Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination. Proc. Natl. Acad. Sci. USA 102: 13242-13247.
86. Andrews, N.P., H. Fujii, J.J. Goronzy & C.M. Weyand. 2010. Telomeres and immunological diseases of aging. Gerontology 56: 390-403.
87. Vajdic, C.M., L. Mao, M.T. van Leeuwen, et al. 2010. Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency? Blood 116: 1228-1234.
88. Salavoura, K., A. Kolialexi, G. Tsangaris & A. Mavrou. 2008. Development of cancer in patients with primary immunodeficiencies. Anticancer Res. 28: 1263-1269.
89. Filipovich, A.H., A. Mathur, D. Kamat & R.S. Shapiro. 1992. Primary immunodeficiencies: genetic risk factors for lymphoma. Cancer Res. 52: 5465s-5467s.
90. Jankovic, M., A. Nussenzweig & M.C. Nussenzweig. 2007. Antigen receptor diversification and chromosome translocations. Nat. Immunol. 8: 801-808.
91. Edry, E. & D. Melamed. 2007. Class switch recombination: a friend and a foe. Clin. Immunol. 123: 244-251.
92. Rezaei, N., M. Hedayat, A. Aghamohammadi & K.E. Nichols. 2011. Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies. J. Allergy Clin. Immunol. 127: 1329-1341.
93. Mellemkjaer, L., L. Hammarstrom, V. Andersen, et al. 2002. Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study. Clin. Exp. Immunol. 130: 495-500.
94. Arana, M.E. & T.A. Kunkel. 2010. Mutator phenotypes due to DNA replication infidelity. Semin. Cancer Biol. 20: 304-311.
95. Chun, H.H. & R.A. Gatti. 2004. Ataxia-telangiectasia, an evolving phenotype. DNA Repair (Amst). 3: 1187-1196.
96. Aurias, A., B. Dutrillaux, D. Buriot & J. Lejeune. 1980. High frequencies of inversions and translocations of chromosomes 7 and 14 in ataxia telangiectasia. Mutat. Res. 69: 369-374.
97. Vacchio, M.S., A. Olaru, F. Livak & R.J. Hodes. 2007. ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor alpha locus coding end breaks. Proc. Natl. Acad. Sci. USA 104: 6323-6328.
98. Bredemeyer, A.L., G.G. Sharma, C.Y. Huang, et al. 2006. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 442: 466-470.
99. Pan, Q., C. Petit-Frere, A. Lahdesmaki, et al. 2002. Alternative end joining during switch recombination in patients with ataxia-telangiectasia. Eur. J. Immunol. 32: 1300-1308.
100. Khanna, K.K. 2000. Cancer risk and the ATM gene: a continuing debate. J. Natl. Cancer Inst. 92: 795-802.
101. Shiloh, Y. 1997. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu. Rev. Genet. 31: 635-662.
102. Difilippantonio, S., A. Celeste, O. Fernandez-Capetillo, et al. 2005. Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nat. Cell Biol. 7: 675-685.
103. Kracker, S., Y. Bergmann, I. Demuth, et al. 2005. Nibrin functions in Ig class-switch recombination. Proc. Natl. Acad. Sci. USA 102: 1584-1589.
104. Reina-San-Martin, B., M.C. Nussenzweig, A. Nussenzweig & S. Difilippantonio. 2005. Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc. Natl. Acad. Sci. USA 102: 1590-1595.
105. Harfst, E., S. Cooper, S. Neubauer, et al. 2000. Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome. Mol. Immunol. 37: 915-929.
106. Dinkelmann, M., E. Spehalski, T. Stoneham, et al. 2009. Multiple functions of MRN in end-joining pathways during isotype class switching. Nat. Struct. Mol. Biol. 16: 808-813.
107. Ferguson, D.O. & F.W. Alt. 2001. DNA double strand break repair and chromosomal translocation: lessons from animal models. Oncogene 20: 5572-5579.
108. Rooney, S., J. Sekiguchi, S. Whitlow, et al. 2004. Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. Proc. Natl. Acad. Sci. USA 101: 2410-2415.
109. Frank, K.M., N.E. Sharpless, Y. Gao, et al. 2000. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol. Cell 5: 993-1002.
110. Harrison, C., A.M. Ketchen, N.J. Redhead, et al. 2002. Replication failure, genome instability, and increased cancer susceptibility in mice with a point mutation in the DNA ligase I gene. Cancer Res. 62: 4065-4074.
111. Furuichi, Y. 2001. Premature aging and predisposition to cancers caused by mutations in RecQ family helicases. Ann. N. Y. Acad. Sci. 928: 121-131.
112. Vijayalaxmi, H., J. Evans, J.H. Ray & J. German. 1983. Bloom's syndrome: evidence for an increased mutation frequency in vivo. Science 221: 851-853.
113. Hickson, I.D. 2003. RecQ helicases: caretakers of the genome. Nat. Rev. Cancer 3: 169-178.
114. Kunkel, T.A. & D.A. Erie. 2005. DNA mismatch repair. Annu. Rev. Biochem. 74: 681-710.
115. Zha, S., C. Guo, C. Boboila, et al. 2011. ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks. Nature 469: 250-254.
116. Li, G., F.W. Alt, H.L. Cheng, et al. 2008. Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination. Mol. Cell 31: 631-640.
117. Jhappan, C., H.C. Morse, III, R.D. Fleischmann, et al. 1997. DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. Nat. Genet. 17: 483-486.
118. Stracker, T.H. & J.H. Petrini. 2011. The MRE11 complex: starting from the ends. Nat. Rev. Mol. Cell Biol. 12: 90-103.
119. Uchisaka, N., N. Takahashi, M. Sato, et al. 2009. Two brothers with ataxia-telangiectasia-like disorder with lung adenocarcinoma. J. Pediatr. 155: 435-438.
120. Theunissen, J.W., M.I. Kaplan, P.A. Hunt, et al. 2003. Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11(ATLD1/ATLD1) mice. Mol. Cell 12: 1511-1523.
121. Bohgaki, T., M. Bohgaki, R. Cardoso, et al. 2011. Genomic instability, defective spermatogenesis, immunodeficiency, and cancer in a mouse model of the RIDDLE syndrome. PLoS Genet. 7: e1001381.
122. Ahmed, M. & N. Rahman. 2006. ATM and breast cancer susceptibility. Oncogene 25: 5906-5911.
123. Dzikiewicz-Krawczyk, A. 2008. The importance of making ends meet: mutations in genes and altered expression of proteins of the MRN complex and cancer. Mutat. Res. 659: 262-273.
124. Ciara, E., D. Piekutowska-Abramczuk, E. Popowska, et al. 2010. Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. Acta Neuropathol. 119: 325-334.
125. Gumy-Pause, F., P. Wacker & A.P. Sappino. 2004. ATM gene and lymphoid malignancies. Leukemia 18: 238-242.
126. Kerangueven, F., F. Eisinger, T. Noguchi, et al. 1997. Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions. Oncogene 14: 339-347.
127. Koike, M., S. Takeuchi, S. Park, et al. 1999. Ovarian cancer: loss of heterozygosity frequently occurs in the ATM gene, but structural alterations do not occur in this gene. Oncology 56: 160-163.
128. Cybulski, C., B. Gorski, T. Debniak, et al. 2004. NBS1 is a prostate cancer susceptibility gene. Cancer Res. 64: 1215-1219.
129. Gorski, B., T. Debniak, B. Masojc, et al. 2003. Germline 657del5 mutation in the NBS1 gene in breast cancer patients. Int. J. Cancer 106: 379-381.
130. Plisiecka-Halasa, J., A. Dansonka-Mieszkowska, A. Rembiszewska, et al. 2002. Nijmegen breakage syndrome gene (NBS1) alterations and its protein (nibrin) expression in human ovarian tumours. Ann. Hum. Genet. 66: 353-359.
131. Gruber, S.B., N.A. Ellis, K.K. Scott, et al. 2002. BLM heterozygosity and the risk of colorectal cancer. Science 297: 2013.
132. Calin, G., G.N. Ranzani, D. Amadori, et al. 2001. Somatic frameshift mutations in the Bloom syndrome BLM gene are frequent in sporadic gastric carcinomas with microsatellite mutator phenotype. BMC Genet. 2: 14.
133. D'Andrea, A.D. 2010. Susceptibility pathways in Fanconi's anemia and breast cancer. N. Engl. J. Med. 362: 1909-1919.
134. Seal, S., D. Thompson, A. Renwick, et al. 2006. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat. Genet. 38: 1239-1241.
135. Hellebrand, H., C. Sutter, E. Honisch, et al. 2011. Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. Hum. Mutat. 32: E2176-E2188.
136. Cleton-Jansen, A.M., N. Collins, S.R. Lakhani, et al. 1995. Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13. Br. J. Cancer 72: 1241-1244.
137. Hilton, J.L., J.P. Geisler, J.A. Rathe, et al. 2002. Inactivation of BRCA1 and BRCA2 in ovarian cancer. J. Natl. Cancer Inst. 94: 1396-1406.
138. Lancaster, J.M., R. Wooster, J. Mangion, et al. 1996. BRCA2 mutations in primary breast and ovarian cancers. Nat. Genet. 13: 238-240.
139. Lynch, H.T., P.M. Lynch, S.J. Lanspa, et al. 2009. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin. Genet. 76: 1-18.
140. Cunningham, J.M., E.R. Christensen, D.J. Tester, et al. 1998. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 58: 3455-3460.
141. Dombernowsky, S.L., M. Weischer, K.H. Allin, et al. 2008. Risk of cancer by ATM missense mutations in the general population. J. Clin. Oncol. 26: 3057-3062.
142. Boultwood, J. 2001. Ataxia telangiectasia gene mutations in leukaemia and lymphoma. J. Clin. Pathol. 54: 512-516.
143. Andreae, J., R. Varon, K. Sperling & K. Seeger. 2007. Polymorphisms in the DNA ligase IV gene might influence the risk of acute lymphoblastic leukemia in children. Leukemia 21: 2226-2227.
144. Pearce, C.L., A.M. Near, D.J. Van Den Berg, et al. 2009. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium. Br. J. Cancer 100: 412-420.
145. Tseng, R.C., F.J. Hsieh, C.M. Shih, et al. 2009. Lung cancer susceptibility and prognosis associated with polymorphisms in the nonhomologous end-joining pathway genes: a multiple genotype-phenotype study. Cancer 115: 2939-2948.
146. Cleary, S.P., W. Zhang, N.N. Di, et al. 2003. Heterozygosity for the BLM(Ash) mutation and cancer risk. Cancer Res. 63: 1769-1771.
147. Berwick, M., J.M. Satagopan, L. Ben-Porat, et al. 2007. Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer. Cancer Res. 67: 9591-9596.
148. Mathew, C.G. 2006. Fanconi anaemia genes and susceptibility to cancer. Oncogene 25: 5875-5884.
149. Dembowska-Baginska, B., D. Perek, A. Brozyna, et al. 2009. Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr. Blood Cancer 52: 186-190.
150. Kutler, D.I., A.D. Auerbach, J. Satagopan, et al. 2003. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch. Otolaryngol. Head Neck Surg. 129: 106-112.
151. Micol, R., S.L. Ben, F. Suarez, et al. 2011. Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. J. Allergy Clin. Immunol. 128: 382-389.
152. Pollard, J.M. & R.A. Gatti. 2009. Clinical radiation sensitivity with DNA repair disorders: an overview. Int. J. Radiat. Oncol. Biol. Phys. 74: 1323-1331.
153. Shaheen, M., C. Allen, J.A. Nickoloff & R. Hromas. 2011. Synthetic lethality: exploiting the addiction of cancer to DNA repair. Blood 117: 6074-6082.
154. Albert, M.H., A.R. Gennery, J. Greil, et al. 2010. Successful SCT for Nijmegen breakage syndrome. Bone Marrow Transplant. 45: 622-626.
155. Eibel, H., U. Salzer & K. Warnatz. 2010. Common variable immunodeficiency at the end of a prospering decade: towards novel gene defects and beyond. Curr. Opin. Allergy Clin. Immunol. 10: 526-533.
156. Ferreira, R.C., Q. Pan-Hammarstrom, R.R. Graham, et al. 2010. Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency. Nat. Genet. 42: 777-780.
157. Orange, J.S., J.T. Glessner, E. Resnick, et al. 2011. Genome-wide association identifies diverse causes of common variable immunodeficiency. J. Allergy Clin. Immunol. 127: 1360-1367.