Join us   Log in  

PHARMASPIRE - Volume 15, Issue 01,2023 , Jan-March

Pages: 33-40
Print Article   Download XML  Download PDF

Fanconi anemia and risk of diverse types of cancer: An overview

Author: Bintoo Sharma, Ranjeet Kumar, Harsh Tyagi, Nikita Khera, Megha Bajaj

Category: Pharmacy Practice


Fanconi anemia (FA) is a rare genetic disorder caused by a mistake in DNA repair that results in a variety of clinical signs and symptoms with varied incidence, most notably progressive bone marrow loss (depending on the affected gene), congenital abnormalities, and a propensity for malignancy. Cancer-prone FA is an unusual condition caused by alterations in at least 22 genes. DNA repair, in particular interstrand DNA crosslink (ICL) repair, is associated with the FA pathway. Cellular susceptibility to DNA cross-linking substances like diepoxybutane is a feature of FA. The report was mailed to 34 Fanconi Canada participants in August 2000 who also had FA confirmed by chromosomal breakage. FA is more prevalent among Spanish Gypsies, Afrikaners, and Ashkenazi Jews in addition to being more prevalent among Ashkenazi Jews. The bone marrow failure of FA can be effectively treated with androgens and hematological growth factors, but the majority of patients develop resistance to these medications. Hematopoietic stem cell transplantation is an option for these patients if a donor is available.

Keywords: Ataxia telangiectasia mutated related, Bone marrow transplantation, Bone marrow failure, Diepoxybutane, FA-BRCA pathway, Fanconi anemia, Implantation genetic diagnosis, Monoubiquitination

DOI: 10.56933/Pharmaspire.2023.15106



1. Wiedemann HR. Guido Fanconi (1892-1979) in memoriam. Eur J Pediatr 1979;32:131-2.
2. Mamrak NE, Shimamura A, Howlett NG. Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia. Blood Rev 2017;31:93-9.
3. Alter BP. The bone marrow failure syndromes. In: Hematology of Infancy and Childhood. Philadelphia, PA: WB Saunders Co.; 1993. p. 216-316.
4. Swift MR, Hirschhorn K. Fanconi’s anemia: Inherited susceptibility to chromosome breakage in various tissues. Ann Intern Med 1966;65:496-503.
5. Rosenberg PS, Tamary H, Alter BP. How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi anemia in the United States and Israel. Am J Med Genet Part A 2011;155:1877-83.6. Degan P, Cappelli E, Regis S, Ravera S. New insights and perspectives in. Fanconi anemia research. Trends Mol Med 2019;25:167-70.
7. Auerbach AD. Diagnosis of Fanconi anemia by diepoxybutane analysis. Curr Protoc Hum Genet 2003;37:8-7.
8. Taylor AM, Rothblum-Oviatt C, Ellis NA, Hickson ID, Meyer S, Crawford TO, et al. Chromosome instability syndromes. Nat Rev Dis Prim 2019;5:1-20.
9. Huck K, Hanenberg H, Gudowius S, Fenk R, Kalb R, Neveling K, et al. Delayed diagnosis and complications of Fanconi anemia at an advanced age-a paradigm. Br J Haematol 2006;133:188-97.
10. Neveling K, Endt D, Hoehn H, Schindler D. Genotypephenotype correlations in Fanconi anemia. Mutat Res 2009;668:73-91.
11. Fiesco-Roa MO, Giri N, McReynolds LJ, Best AF, Alter BP. Genotype-phenotype associations in Fanconi anemia: A literature review. Blood Rev 2019;37:100589.
12. Knies K, Inano S, Ramírez MJ, Ishiai M, Surrallés J, Takata M, et al. Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia. J Clin Invest 2017;127:3013-27.
13. Niraj J, Färkkilä A, D’Andrea AD. The Fanconi anemia pathway in cancer. Annu Rev Cancer Biol 2019;3:457-78.
14. Wang AT, Kim T, Wagner JE, Conti BA, Lakh FP, Huang AL, et al. A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination. Mol Cell 2015;59:478-90.
15. Ceccaldi R, Sarangi P, D’Andrea AD. The Fanconi anemia pathway: New players and new functions. Nat Rev Mol Cell Biol 2016;17:337-49.
16. Bhandari J, Thada PK, Puckett Y. Fanconi anemia. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2022.
17. Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev 2010;24:101-22.
18. Wang W. The emergence of a DNA-damage response network consisting of Fanconi anemia and BRCA proteins. Nat Rev Genet 2007;8:735-48.
19. Ciccia A, Ling C, Coulthard R, Yan Z, Xue Y, Meetei AR, et al. Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Mol Cell 2007;25:331-43.
20. Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald 3rd ER, Hurov KE, Luo J, et al. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 2007;129:289-301.
21. Andreassen PR, D’Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA damage response. Genes Dev 2004;18:1958-63.
22. Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, et al. FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat Struct Mol Biol 2008;15:1138-46.
23. Estren S, Dameshek W. Familial hypoplastic anemia of childhood: Report of eight cases in two families with the beneficial effect of splenectomy in one case. Am J Dis Child 1947;73:671-87.
24. Rossbach HC, Sutcliffe MJ, Haag MM, Grana NH, Rossi AR, Barbosa JL. Fanconi anemia in brothers initially diagnosed with VACTERL association with hydrocephalus, and subsequently with Baller-Gerold syndrome. Am J Med Genet 1996;61:65-7.
25. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood 2003;101:822-6.
26. Socié G, Devergie A, Girinski T, Piel G, Ribaud P, Esperou H, et al. Transplantation for Fanconi’s anemia: Long-term follow-up of fifty patients transplanted from a sibling donor after low-dose cyclophosphamide and thoraco-abdominal irradiation for conditioning. Br J Haematol 1998;103:249-55.
27. Dong H, Nebert DW, Bruford EA, Thompson DC, Joenje H, Vasiliou V. Update of the human and mouse Fanconi anemia genes. Hum Genomics 2015;9:32.
28. Deans AJ, West SC. DNA interstrand crosslink repair and cancer. Nat Rev Cancer 2011;11:467-80.
29. Nalepa G, Clapp DW. Fanconi anemia and cancer: An intricate relationship. Nat Rev Cancer 2018;18:168-85.
30. Stone MP, Cho YJ, Huang H, Kim HY, Kozekov ID, Kozekova A, et al. Interstrand DNA cross-links induced by α, β-unsaturated aldehydes derived from lipid peroxidation and environmental sources. Acc Chem Res 2008l;41:793-804.
31. Dokal I, Vulliamy T. Inherited bone marrow failure syndromes. Haematologica 2010;95:1236.
32. Aymun U, Iram S, Aftab I, Khaliq S, Ali N, Ahmed N, et al. Screening for mutations in two exons of FANCG gene in Pakistani population. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2017;161:158-63.
33. Mehta PA, Tolar J. Fanconi Anemia. 2018. Available from: [Last accessed on 2022 Aug 30].
34. Gille JJ, Floor K, Kerkhoven L, Ameziane N, Joenje H, de Winter JP. Diagnosis of Fanconi anemia: Mutation analysis by multiplex ligation-dependent probe amplification and PCR-based Sanger sequencing. Anemia 2012;2012:603253.
35. Callén E, Casado JA, Tischkowitz MD, Bueren JA, Creus A, Marcos R, et al. A common founder mutationn in FANCA underlies the world’s highest prevalence of Fanconi anemia in Gypsy families from Spain. Blood 2005;105:1946-9.
36. Kutler DI, Singh B, Satagopan J, Batish SD, Berwick M, Giampietro PF, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 2003;101:1249-56.
37. Gluckman E, Auerbach AD, Horowitz MM, Sobocinski KA, Ash RC, Bortin MM, et al. Bone marrow transplantation for Fanconi anemia. Blood 1995;86:2856-62.
38. Ebens CL, DeFor TE, Tryon R, Wagner JE, MacMillan ML. Comparable outcomes after HLAmatched sibling and alternative donor hematopoietic cell transplantation for children with Fanconi anemia and severe aplastic anemia. Biol Blood Marrow Transplant 2018;24:765-71.
39. Giri N, Batista DL, Alter BP, Stratakis CA. Endocrine abnormalities in patients with Fanconi anemia. J Clin Endocrinol Metab 2007;92:2624-31.
40. Elder DA, D’Alessio DA, Eyal O, Mueller R, Smith FO, et al. Abnormalities in glucose tolerance are common in children with Fanconi anemia and are associated with impaired insulin secretion. Pediatr Blood Cancer 2008;51:256-60.
41. Butturini A, Gale RP, Verlander PC, Adler-Brecher B, Gillio AP, Auerbach AD. Hematologic abnormalities in Fanconi anemia: An International Fanconi Anemia Registry study. Blood 1994;84:1650-5.
42. Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer 2003;97:425-40.
43. Rosenberg PS, Socié G, Alter BP, Gluckman E. Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood 2005;105:67-73.
44. Su X, Huang J. The Fanconi anemia pathway and DNA interstrand cross-link repair. Protein Cell 2011;2:704-11.
45. Visconti R, Grieco D. New insights on oxidative stress in cancer. Curr Opin Drug Discov Dev 2009;12:240-5.
46. Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen 2017;58:235-63.
47. Collis SJ, Boulton SJ. FANCM: Fork pause, rewind, and play. EMBO J 2010;29:703-5.
48. Schärer OD. DNA interstrand crosslinks: Natural and drug-induced DNA adducts that induce unique cellular responses. Chembiochem 2005;6:27-32.
49. Niedzwiedz W, Mosedale G, Johnson M, Ong CY, Pace P, Patel KJ. The Fanconi anemia gene FANCC promotes homologous recombination and error-prone DNA repair. Mol Cell 2004;15:607-20.
50. Ling C, Ishii M, Ali AM, Medhurst AL, Neveling K, Kalb R, et al. FAAP100 is essential for the activation of the Fanconi anemia-associated DNA damage response pathway. EMBO J 2007;26:2104-14.
51. Matsushita N, Kitao H, Ishiai M, Nagashima N, Hirano S, Okawa K, et al. A FancD2-monoubiquitin fusion reveals hidden functions of Fanconi anemia core complex in DNA repair. Mol Cell 2005;19:841-7.
52. Ciccia A, Elledge SJ. The DNA damage response: Making it safe to play with knives. Mol Cell 2010;40:179-204.
53. Pichierri P, Rosselli F. The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATRNBS1- FANCD2 pathways. EMBO J 2004;23:1178-87.
54. Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ. Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature 2011;475:5358.
55. Rosado IV, Langevin F, Crossan GP, Takata M, Patel KJ. Formaldehyde catabolism is essential in cells deficient for the Fanconi anemia DNA-repair pathway. Nat Struct Mol Biol 2011;18:1432-4.
56. Chen CC, Feng W, Lim PX, Kass EM, Jasin M. Homology-directed repair and the role of BRCA1, BRCA2, and related proteins in genome integrity and cancer. Annu Rev Cancer Biol 2018;2:313-36.

57. Venkitaraman AR. Cancer suppression by the chromosome custodians, BRCA1 and BRCA2. Science 2014;343:1470-5.
58. Dan C, Pei H, Zhang B, Zheng X, Ran D, Du C. Fanconi anemia pathway and its relationship with cancer. Genome Instab Dis 2021;2:175-83.
59. Verlinsky Y, Rechitsky S, Schoolcraft W, Strom C, Kuliev A. Preimplantation diagnosis for Fanconi anemia combined with HLA matching. JAMA 2001;285:3130-3.
60. Mankad A, Taniguchi T, Cox B, Akkari Y, Rathbun RK, Lucas L, et al. Natural gene therapy in monozygotic twins with Fanconi anemia. Blood 2006;107:3084-90.
61. Gregory JJ Jr., Wagner JE, Verlander PC, Levran O, Batish SD, Eide CR, et al. Somatic mosaicism in Fanconi anemia: Evidence of genotypic reversion in lymphohematopoietic stem cells. Proc Natl Acad Sci 2001;98:2532-7.
62. Gluckman E. Radiosensitivity in Fanconi anemia: Application to the conditioning for bone marrow transplantation. Radiother Oncol 1990;18:88-93.
63. Alter BP. Fanconi’s anemia, transplantation, and cancer. Pediatr Transplant 2005;9(Suppl 7):81-6.
64. Alter BP, Rosenberg PS. Natural history and management of Fanconi Anemia patients with head and neck cancer: A 10-year follow-up. Laryngoscope 2016;126:E229.
65. Giampietro PF, Verlander PC, Davis JG, Auerbach AD. Diagnosis of Fanconi anemia in patients without congenital malformations: An international Fanconi Anemia Registry Study. Am J Med Genet 1997;68:58-61.
66. Lach FP, Singh S, Rickman KA, Ruiz PD, Noonan RJ, Hymes KB, et al. Esophageal cancer as the initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant. Cold Spring Harb Mol Case Stud 2020;6:a005595.
67. Royce M, Osgood CL, Amatya AK, Fiero MH, Chang CG, Ricks TK, et al. FDA approval summary: Margetuximab plus chemotherapy for advanced or metastatic HER2- positive breast cancer. Clin Cancer Res 2022;28:1487-92.
68. Auerbach AD. Fanconi anemia and its diagnosis. Mutat Res 2009;668:4-10.
69. Seyschab H, Friedl R, Sun Y, Schindler D, Hoehn H, Hentze S, et al. Comparative evaluation of diepoxybutane sensitivity and cell cycle blockage in the diagnosis of Fanconi anemia. Blood 1995;85:2233-7.
70. Shimamura A, de Oca RM, Svenson JL, Haining N, Moreau LA, Nathan DG, et al. A novel diagnostic screen for defects in the Fanconi anemia pathway. Blood 2002;100:4649-54.
71. Gutiontov SI, Shin EJ, Lok B, Lee NY, Cabanillas R. Intensity-modulated radiotherapy for head and neck surgeons. Head Neck 2016;38(S1):E2368-73.
72. Mehanna H, Robinson M, Hartley A, Kong A, Foran B, Fulton-Lieuw T, et al. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): An open-label randomized controlled phase 3 trial. Lancet 2019;393:51-60.
73. Velazquez I, Alter BP. Androgens and liver tumors: Fanconi’s anemia and non-Fanconi’s conditions. Am J Hematol 2004;77:257-67.
74. Scheckenbach K, Morgan M, Filger-Brillinger J, Sandmann M, Strimling B, Scheurlen W, et al. Treatment of the bone marrow failure in Fanconi anemia patients with danazol. Blood Cells Mol Dis 2012;48:128-31.
75. Rio P, Navarro S, Bueren JA. Advances in gene therapy for Fanconi anemia. Hum Gene Ther 2018;29:1114-23.
76. Sharma P, Sharma N, Sharma D. A narrative review on Fanconi Anemia: Genetic and diagnostic considerations. Glob Med Genet 2022;9:237-41.
77. Burroughs L, Woolfrey A, Shimamura A. Shwachman- Diamond syndrome: A review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am 2009;23:233-48.
78. Mehta PA, Ebens C. Fanconi Anemia Synonym: Fanconi Pancytopenia. United States: National Center for Biotechnology Information, US National Library of Medicine.
79. Alter BP, Caruso JP, Drachtman RA, Uchida T, Velagaleti GV, Elghetany MT. Fanconi anemia: Myelodysplasia as a predictor of outcome. Cancer Genet Cytogenet 2000;117:125-31.
80. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, de Die-Smulders C, et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 2002;297:606-9.
81. Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med 2008;359:2143-53.
82. Stratton MR, Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet 2008;40:17-22.
83. Lancaster JM, Wooster R, Mangion J, Phelan CM, Cochran C, Gumbs C, et al. BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 1996;13:238-40.
84. Kennedy RD, D’Andrea AD. The Fanconi Anemia/ BRCA pathway: New faces in the crowd. Genes Dev 2005;19:2925-40.
85. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui- Roelvink M, et al. Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123-34.
86. Liu W, Palovcak A, Li F, Zafar A, Yuan F, Zhang Y. Fanconi anemia pathway as a prospective target for cancer intervention. Cell Biosci 2020;10:39.
87. Ghosh A, Ghosh S, Maiti GP, Mukherjee S, Mukherjee N, Chakraborty J, et al. Association of FANCC and PTCH1 with the development of early dysplastic lesions of the head and neck. Ann Surg Oncol 2012;19(Suppl 3):528-38.
88. Szaumkessel M, Richter J, Giefing M, Jarmuz M, Kiwerska K, Tönnies H, et al. Pyrosequencing-based DNA methylation profiling of Fanconi anemia/BRCA pathway genes in laryngeal squamous cell carcinoma. Int J Oncol 2011;39:505-14.
89. Hess CJ, Ameziane N, Schuurhuis GJ, Errami A, Denkers F, Kaspers GJ, et al. Hypermethylation of the FANCC and FANCL promoter regions in sporadic acute leukemia. Anal Cell Pathol 2008;30:299-306.