Skip to main content

The Fanconi anaemia/BRCA pathway and cancer susceptibility. Searching for new therapeutic targets

Clinical and Translational Oncology volume 10, pages 78–84 (2008)Cite this article

Abstract

Breast cancer is one of the most frequent cancers in the world. The majority of cases are sporadic but around 15% show some type of familial aggregation and about 5% exhibit a clear hereditary pattern. Common and rare low-moderate-penetrance genes, and high-penetrance genes are thought to explain the genetic susceptibility to the disease. Only around 20% of the inherited risk to breast cancer is explained by germline mutations in the known high-penetrance susceptibility genes BRCA1 and BRCA2. Mutations in genes such as TP53 and PTEN have also been linked with high risk for breast cancer within specific cancer syndromes and rare germline variants in genes such as CHEK2 and ATM have been found to confer modest risk to breast cancer. However, we can say that less than 30% of familial risk of breast cancer is due to known genes. Identification in 2002 of the Fanconi anaemia (FA) gene FANCD1 as BRCA2 and recent studies indicating that heterozygous mutations in FANCN/PALB2 and FANCJ/ BRIP1 predispose to breast cancer have emphasised an important connection between the FA and BRCA pathway. Here we review the emerging DNA-damage response network consisting of FA and BRCA proteins, summarise what is currently known about the direct involvement of these molecules in breast cancer susceptibility and discuss the prospect offered by this pathway in order to identify more breast cancer related genes. We finally present the current stage of therapeutic options specifically targeting the FA/BRCA pathway and summarise the challenges this field encounters

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  1. Lopez-Abente G, Pollan M, Aragones N et al (2004) [State of cancer in Spain: incidence]. An Sist Sanit Navar 27:165–173

    PubMed  CAS  Google Scholar 

  2. Houlston RS, Peto J (2004) The search for low-penetrance cancer susceptibility alleles. Oncogene 23:6471–6476

    PubMed  Article  CAS  Google Scholar 

  3. Easton DF, Pooley KA, Dunning AM et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447: 1087–1093

    PubMed  Article  CAS  Google Scholar 

  4. Stacey SN, Manolescu A, Sulem P et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39:865–869

    PubMed  Article  CAS  Google Scholar 

  5. Milne RL, Ribas G, Gonzalez-Neira A et al (2006) ERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping. Cancer Res 66:9420–9427

    PubMed  Article  CAS  Google Scholar 

  6. Thompson D, Antoniou AC, Jenkins M et al (2005) Two ATM variants and breast cancer risk. Hum Mutat 25:594–595

    PubMed  Article  Google Scholar 

  7. Meijers-Heijboer H, van den Ouweland A, Klijn J et al (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in non-carriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55–59

    PubMed  Article  CAS  Google Scholar 

  8. Johnson N, Fletcher O, Palles C et al (2007) Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum Mol Genet 16:1051–1057

    PubMed  Article  CAS  Google Scholar 

  9. Antoniou AC, Pharoah PD, McMullan G et al (2001) Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genet Epidemiol 21:1–18

    PubMed  Article  CAS  Google Scholar 

  10. Diez O, Osorio A, Duran M et al (2003) Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum Mutat 22:301–312

    PubMed  Article  CAS  Google Scholar 

  11. Ford D, Easton DF (1995) The genetics of breast and ovarian cancer. Br J Cancer 72:805–812

    PubMed  CAS  Google Scholar 

  12. Chen S, Parmigiani G (2007) Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25:1329–1333

    PubMed  Article  Google Scholar 

  13. Antoniou A, Pharoah PD, Narod S et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:1117–1130

    PubMed  Article  CAS  Google Scholar 

  14. García MJ, Fernández V, Osorio A, et al. Analysis of FANCB and FANCN/ PALB2 Fanconi Anemia genes in BRCA1/2-negative Spanish breast cancer families (submitted)

  15. Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182

    PubMed  Article  CAS  Google Scholar 

  16. Yoshida K, Miki Y (2004) Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci 95:866–871

    PubMed  Article  CAS  Google Scholar 

  17. Kim H, Chen J, Yu X (2007) Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316:1202–1205

    PubMed  Article  CAS  Google Scholar 

  18. Sobhian B, Shao G, Lilli DR et al (2007) RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316:1198–1202

    PubMed  Article  CAS  Google Scholar 

  19. Wang B, Matsuoka S, Ballif BA et al (2007) Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316:1194–1198

    PubMed  Article  CAS  Google Scholar 

  20. Lu H, Guo X, Meng X et al (2005) The BRCA2-interacting protein BCCIP functions in RAD51 and BRCA2 focus formation and homologous recombinational repair. Mol Cell Biol 25:1949–1957

    PubMed  Article  CAS  Google Scholar 

  21. Joenje H, Patel KJ (2001) The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet 2:446–457

    PubMed  Article  CAS  Google Scholar 

  22. Hirano S, Yamamoto K, Ishiai M et al (2005) Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM. EMBO J 24:418–427

    PubMed  Article  CAS  Google Scholar 

  23. Akkari YM, Bateman RL, Reifsteck CA et al (2000) DNA replication is required to elicit cellular responses to psoralen-induced DNA interstrand cross-links. Mol Cell Biol 20:8283–8289

    PubMed  Article  CAS  Google Scholar 

  24. Wang W (2007) Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet 8:735–748

    PubMed  Article  CAS  Google Scholar 

  25. Callen E, Casado JA, Tischkowitz MD et al (2005) A common founder mutation in FANCA underlies the world’s highest prevalence of Fanconi anemia in Gypsy families from Spain. Blood 105:1946–1949

    PubMed  Article  CAS  Google Scholar 

  26. Verlander PC, Kaporis A, Liu Q et al (1995) Carrier frequency of the IVS4 + 4 A→T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population. Blood 86:4034–4038

    PubMed  CAS  Google Scholar 

  27. Strathdee CA, Gavish H, Shannon WR, Buchwald M (1992) Cloning of cDNAs for Fanconi’s anaemia by functional complementation. Nature 358:434

    PubMed  CAS  Google Scholar 

  28. Medhurst AL, Huber PA, Waisfisz Q et al (2001) Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway. Hum Mol Genet 10:423–429

    PubMed  Article  CAS  Google Scholar 

  29. Timmers C, Taniguchi T, Hejna J et al (2001) Positional cloning of a novel Fanconi anemia gene, FANCD2. Mol Cell 7:241–248

    PubMed  Article  CAS  Google Scholar 

  30. Sims AE, Spiteri E, Sims RJ 3rd et al (2007) FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol 14:564–567

    PubMed  Article  CAS  Google Scholar 

  31. Dorsman JC, Levitus M, Rockx D et al (2007) Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol 29:211–218

    PubMed  CAS  Google Scholar 

  32. Howlett NG, Taniguchi T, Olson S et al (2002) Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297:606–609

    PubMed  Article  CAS  Google Scholar 

  33. Alter BP, Rosenberg PS, Brody LC (2007) Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet 44:1–9

    PubMed  Article  CAS  Google Scholar 

  34. Seal S, Barfoot R, Jayatilake H et al (2003) Evaluation of Fanconi Anemia genes in familial breast cancer predisposition. Cancer Res 63:8596–8599

    PubMed  CAS  Google Scholar 

  35. Seal S, Thompson D, Renwick A et al (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38:1239–1241

    PubMed  Article  CAS  Google Scholar 

  36. Xia B, Sheng Q, Nakanishi K et al (2006) Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 22:719–729

    PubMed  Article  CAS  Google Scholar 

  37. Xia B, Dorsman JC, Ameziane N et al (2007) Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nat Genet 39:159–161

    PubMed  Article  CAS  Google Scholar 

  38. Reid S, Schindler D, Hanenberg H et al (2007) Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39:162–164

    PubMed  Article  CAS  Google Scholar 

  39. Rahman N, Seal S, Thompson D et al (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39:165–167

    PubMed  Article  CAS  Google Scholar 

  40. Tischkowitz M, Xia B, Sabbaghian N et al (2007) Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci U S A 104: 6788–6793

    PubMed  Article  CAS  Google Scholar 

  41. Milne RL, Osorio A, Ramón y Cajal T, et al. The average cumulative risks of breast and ovarian cancer for carriers of mutations in BRCA1 and BRCA2 attending genetic counselling units in Spain. Clinical Cancer Research (in press)

  42. Erkko H, Xia B, Nikkila J et al (2007) A recurrent mutation in PALB2 in Finnish cancer families. Nature 446:316–319

    PubMed  Article  CAS  Google Scholar 

  43. Kim H, Huang J, Chen J (2007) CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response. Nat Struct Mol Biol 14:710–715

    PubMed  Article  CAS  Google Scholar 

  44. van der Heijden MS, Yeo CJ, Hruban RH, Kern SE (2003) Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res 63: 2585–2588

    PubMed  Google Scholar 

  45. van der Heijden MS, Brody JR, Gallmeier E et al (2004) Functional defects in the Fanconi anemia pathway in pancreatic cancer cells. Am J Pathol 165: 651–657

    PubMed  Google Scholar 

  46. Couch FJ, Johnson MR, Rabe K et al (2005) Germ line Fanconi anemia complementation group C mutations and pancreatic cancer. Cancer Res 65:383–386

    PubMed  CAS  Google Scholar 

  47. Taniguchi T, Tischkowitz M, Ameziane N et al (2003) Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med 9:568–574

    PubMed  Article  CAS  Google Scholar 

  48. Narayan G, Arias-Pulido H, Nandula SV et al (2004) Promoter hypermethylation of FANCF: disruption of Fanconi Anemia-BRCA pathway in cervical cancer. Cancer Res 64:2994–2997

    PubMed  Article  CAS  Google Scholar 

  49. Marsit CJ, Liu M, Nelson HH et al (2004) Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. Oncogene 23:1000–1004

    PubMed  Article  CAS  Google Scholar 

  50. Jacinto FV, Esteller M (2007) Mutator pathways unleashed by epigenetic silencing in human cancer. Mutagenesis 22:247–253

    PubMed  Article  CAS  Google Scholar 

  51. Rio PG, Pernin D, Bay JO et al (1998) Loss of heterozygosity of BRCA1, BRCA2 and ATM genes in sporadic invasive ductal breast carcinoma. Int J Oncol 13:849–853

    PubMed  CAS  Google Scholar 

  52. Katsama A, Sourvinos G, Zachos G, Spandidos DA (2000) Allelic loss at the BRCA1, BRCA2 and TP53 loci in human sporadic breast carcinoma. Cancer Lett 150:165–170

    PubMed  Article  CAS  Google Scholar 

  53. Gallmeier E, Kern SE (2007) Targeting Fanconi anemia/BRCA2 pathway defects in cancer: the significance of preclinical pharmacogenomic models. Clin Cancer Res 13:4–10

    PubMed  Article  CAS  Google Scholar 

  54. Kennedy RD, Chen CC, Stuckert P et al (2007) Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. J Clin Invest 117:1440–1449

    PubMed  Article  CAS  Google Scholar 

  55. Gallmeier E, Hucl T, Brody JR et al (2007) Highthroughput screening identifies novel agents eliciting hypersensitivity in Fanconi pathway-deficient cancer cells. Cancer Res 67:2169–2177

    PubMed  Article  CAS  Google Scholar 

  56. van der Heijden MS, Brody JR, Dezentje DA et al (2005) In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res 11:7508–7515

    PubMed  Article  Google Scholar 

  57. Nguewa PA, Fuertes MA, Cepeda V et al (2006) Poly(ADP-ribose) polymerase-1 inhibitor 3-aminobenzamide enhances apoptosis induction by platinum complexes in cisplatin-resistant tumor cells. Med Chem 2:47–53

    PubMed  Article  CAS  Google Scholar 

  58. Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917

    PubMed  Article  CAS  Google Scholar 

  59. Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

    PubMed  Article  CAS  Google Scholar 

  60. Schreiber V, Ame JC, Dolle P et al (2002) Poly(ADP-ribose) polymerase-2 (PARP-2) is required for efficient base excision DNA repair in association with PARP-1 and XRCC1. J Biol Chem 277:23028–23036

    PubMed  Article  CAS  Google Scholar 

  61. Boulton S, Kyle S, Durkacz BW (1999) Interactive effects of inhibitors of poly(ADP-ribose) polymerase and DNA-dependent protein kinase on cellular responses to DNA damage. Carcinogenesis 20:199–203

    PubMed  Article  CAS  Google Scholar 

  62. Ratnam K, Low JA (2007) Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology. Clin Cancer Res 13:1383–1388

    PubMed  Article  CAS  Google Scholar 

  63. Rubinstein WS (2007) Hereditary breast cancer: pathobiology, clinical translation, and potential for targeted cancer therapeutics. Fam Cancer. 2007 Jul 12; (Epub ahead of print)

  64. Melchor L, Honrado E, Garcia MJ, Alvarez S, Palacios J, Osorio A, Nathanson KL, Benitez J (2007) Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes. Oncogene. 2007 Dec 10; (Epub ahead of print)

  65. Honrado E, Osorio A, Milne RL et al (2007) Immunohistochemical classification of non-BRCA1/2 tumors identifies different groups that demonstrate the heterogeneity of BRCAX families. Mod Pathol 20:1298–1306

    PubMed  Article  CAS  Google Scholar 

  66. Sorlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869–10874

    PubMed  Article  CAS  Google Scholar 

  67. Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418–8423

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

  1. Group of Human Genetics, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO) and Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, C/ Melchor Fernández Almagro 3, ES-28029, Madrid, Spain

    M. José García & Javier Benítez

Authors
  1. M. José García
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Javier Benítez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Javier Benítez.

Additional information

Supported by an unrestricted educational grant from Pfizer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

García, M.J., Benítez, J. The Fanconi anaemia/BRCA pathway and cancer susceptibility. Searching for new therapeutic targets. Clin Transl Oncol 10, 78–84 (2008). https://doi.org/10.1007/s12094-008-0160-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-008-0160-6

Keywords

  • Fanconi anaemia
  • Breast cancer susceptibility genes
  • BRCA1
  • BRCA2
  • Targeted therapy