Breast Cancer Research and Treatment

, Volume 130, Issue 3, pp 1021–1028 | Cite as

Mutation analysis of the SLX4/FANCP gene in hereditary breast cancer

  • Rosa Landwehr
  • Natalia V. Bogdanova
  • Natalia Antonenkova
  • Andreas Meyer
  • Michael Bremer
  • Tjoung-Won Park-Simon
  • Peter Hillemanns
  • Johann H. Karstens
  • Detlev Schindler
  • Thilo Dörk
Epidemiology

Abstract

SLX4 coordinates three structure-specific endonucleases in the DNA damage response. One subtype of Fanconi anaemia, FA-P, has recently been attributed to biallelic SLX4 gene mutations. To investigate whether monoallelic SLX4 gene defects play some role in the inherited component of breast cancer susceptibility, in this study we resequenced the whole SLX4 coding region and flanking untranslated sections in genomic DNA samples obtained from a total of 52 German or Byelorussian patients with familial breast cancer. Selected variants were subsequently screened by RFLP or TaqMan-based assays in an extended set of 965 German breast cancer cases and 985 healthy female controls. The resequencing study uncovered four new SLX4 missense substitutions, each of them in a single breast cancer patient. Three missense substitutions (p.V197A, p.G700R and p.R1034H) were not found in a subsequent screening of 240 additional breast cancer patients, while one missense substitution (p.R237Q) was more common and was detected in a total of 12 cases (1.3%) and seven controls (0.7%) in the Hannover breast cancer study. The rare missense substitution, p.G700R, resides in the conserved BTB domain and was in silico predicted to be pathogenic. Seven additional missense polymorphisms were correlated and formed one haplotype which was, however, neither associated with breast cancer risk nor with survival from breast cancer. In summary, this study did not reveal truncating or clearly pathogenic mutations, but unravelled four new unclassified missense variants at a low frequency. We conclude that there is no evidence for a major role of SLX4 coding variants in the inherited susceptibility towards breast cancer in German and Byelorussian patients, although very rare mutations such as the p.G700R substitution could make a minor contribution.

Keywords

Breast cancer susceptibility Fanconi anaemia Genetic association studies Crosslink repair DNA damage signalling 

References

  1. 1.
    Fekairi S, Scaglione S, Chahwan C, Taylor ER, Tissier A, Coulon S, Dong MQ, Ruse C, Yates JR 3rd, Russell P, Fuchs RP, McGowan CH, Gaillard PH (2009) Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases. Cell 138:78–89PubMedCrossRefGoogle Scholar
  2. 2.
    Svendsen JM, Smogorzewska A, Sowa ME, O’Connell BC, Gygi SP, Elledge SJ, Harper JW (2009) Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell 138:63–77PubMedCrossRefGoogle Scholar
  3. 3.
    Schwartz EK, Heyer WD (2011) Processing of joint molecule intermediates by structure-selective endonucleases during homologous recombination in eukaryotes. Chromosoma 120(2):109–127PubMedCrossRefGoogle Scholar
  4. 4.
    Yamamoto KN, Kobayashi S, Tsuda M, Kurumizaka H, Takata M, Kono K, Jiricny J, Takeda S, Hirota K (2011) Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway. Proc Natl Acad Sci USA 108(16):6492–6496PubMedCrossRefGoogle Scholar
  5. 5.
    Andersen SL, Bergstralh DT, Kohl KP, LaRocque JR, Moore CB, Sekelsky J (2009) Drosophila MUS312 and the vertebrate ortholog BTBD12 interact with DNA structures-specific endonucleases in DNA repair and recombination. Mol Cell 35:128–135PubMedCrossRefGoogle Scholar
  6. 6.
    Muñoz IM, Hain K, Déclais AC, Gardiner M, Toh GW, Sanchez-Pulido L, Heuckmann JM, Toth R, Macartney T, Eppink B, Kanaar R, Ponting CP, Lilley DM, Rouse J (2009) Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair. Mol Cell 35:116–127PubMedCrossRefGoogle Scholar
  7. 7.
    Flott S, Rouse J (2005) Slx4 becomes phosphorylated after DNA damage in a Mec1/Tel1-dependent manner and is required for repair of DNA alkylation damage. Biochem J 391:325–333PubMedCrossRefGoogle Scholar
  8. 8.
    Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316(5828):1160–1166PubMedCrossRefGoogle Scholar
  9. 9.
    Holloway JK, Mohan S, Balmus G, Sun X, Modzelewski A, Borst PL, Freire R, Weiss RS, Cohen PE (2011) Mammalian BTBD12 (SLX4) protects against genomic instability during mammalian spermatogenesis. PLoS Genet 7(6):e1002094PubMedCrossRefGoogle Scholar
  10. 10.
    Kim Y, Lach FP, Desetty R, Hanenberg H, Auerbach AD, Smogorzewska A (2011) Mutations of the SLX4 gene in Fanconi anemia. Nat Genet 43(2):142–146PubMedCrossRefGoogle Scholar
  11. 11.
    Stoepker C, Hain K, Schuster B, Hilhorst-Hofstee Y, Rooimans MA, Steltenpool J, Oostra AB, Eirich K, Korthof ET, Nieuwint AW, Jaspers NG, Bettecken T, Joenje H, Schindler D, Rouse J, de Winter JP (2011) SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. Nat Genet 43(2):138–141PubMedCrossRefGoogle Scholar
  12. 12.
    Cybulski KE, Howlett NG (2011) FANCP/SLX4: a Swiss army knife of DNA interstrand crosslink repair. Cell Cycle 10:1757–1763PubMedCrossRefGoogle Scholar
  13. 13.
    Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D’Andrea AD (2002) Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297:606–609PubMedCrossRefGoogle Scholar
  14. 14.
    Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D, Breast Cancer Susceptibility Collaboration (UK), Easton DF, Stratton MR (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39(2):165–167PubMedCrossRefGoogle Scholar
  15. 15.
    Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, Chagtai T, Jayatilake H, Ahmed M, Spanova K, North B, McGuffog L, Evans DG, Eccles D, Breast Cancer Susceptibility Collaboration (UK), Easton DF, Stratton MR, Rahman N (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38:1239–1241PubMedCrossRefGoogle Scholar
  16. 16.
    Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E et al (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42:410–414PubMedCrossRefGoogle Scholar
  17. 17.
    Backe J, Hofferbert S, Skawran B, Dörk T, Stuhrmann M, Karstens JH, Untch M, Meindl A, Burgemeister R, Chang-Claude J, Weber BHF (1999) Frequency of BRCA1 mutation 5382insC in German breast cancer patients. Gynecol Oncol 72:402–406PubMedCrossRefGoogle Scholar
  18. 18.
    Dörk T, Bendix R, Bremer M, Rades D, Klöpper K, Nicke M, Skawran B, Hector A, Yamini P, Steinmann D, Weise S, Stuhrmann M, Karstens JH (2001) Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61:7608–7615PubMedGoogle Scholar
  19. 19.
    The CHEK2 Breast Cancer Case-Control Consortium (2004) CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10, 860 breast cancer cases and 9, 065 controls from 10 studies. Am J Hum Genet 74:1175–1182CrossRefGoogle Scholar
  20. 20.
    Bogdanova N, Feshchenko S, Cybulski C, Dörk T (2007) CHEK2 mutation and hereditary breast cancer. J Clin Oncol 95:e26CrossRefGoogle Scholar
  21. 21.
    The Breast Cancer Association Consortium (2006) Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J Natl Cancer Inst 98:1382–1396CrossRefGoogle Scholar
  22. 22.
    Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MWR, Pooley KA, Scollen S, Ponder BAJ, Chanock S, Lissowska J, Brinton L, Southey MC et al (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39:352–358PubMedCrossRefGoogle Scholar
  23. 23.
    Easton DF, Pooley KA, Dunning AM, Pharoah PDP, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, Wareham N, Ahmed S et al (2007) A genome-wide association study identifies breast cancer susceptibility loci. Nature 447:1087–1093PubMedCrossRefGoogle Scholar
  24. 24.
    Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, Platte R, Morrison J, Maranian M, Pooley K, Luben R, Eccles D, Evans DG et al (2009) Novel breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41(5):585–590PubMedCrossRefGoogle Scholar
  25. 25.
    Schmidt MK, Tommiska J, Broeks A, van Leeuwen FE, Van’t Veer LJ, Pharoah PD, Easton DF, Shah M, Humphreys M, Dörk T, Reincke SA, Fagerholm R, Blomqvist C, Nevanlinna H (2009) Combined effects of single nucleotide polymorphisms TP53 R72P and MDM2 SNP309, and p53 expression on survival of breast cancer patients. Breast Cancer Res 11:R89PubMedCrossRefGoogle Scholar
  26. 26.
    Lin WY, Camp NJ, Cannon-Albright LA, Allen-Brady K, Balasubramanian S, Reed MW, Hopper JL, Apicella C, Giles GG, Southey MC, Milne RL, Arias-Pérez JI et al (2011) A role for XRCC2 gene polymorphisms in breast cancer risk and survival. J Med Genet 48:477–484PubMedCrossRefGoogle Scholar
  27. 27.
    Bogdanova N, Enßen-Dubrowinskaja N, Festchenko S, Lazijuk S, Rogov YI, Dammann O, Bremer M, Karstens JH, Sohn C, Dörk T (2005) Association of two mutations in the CHEK2 gene with breast cancer. Int J Cancer 116:263–266PubMedCrossRefGoogle Scholar
  28. 28.
    Bogdanova N, Feshchenko S, Schürmann P, Waltes R, Wieland B, Hillemanns P, Rogov YI, Dammann O, Bremer M, Karstens JH, Sohn C, Varon R, Dörk T (2008) Nijmegen breakage syndrome mutations and risk of breast cancer. Int J Cancer 122(4):802–806PubMedCrossRefGoogle Scholar
  29. 29.
    Bogdanova N, Schürmann P, Waltes R, Feshchenko S, Zalutsky IV, Bremer M, Dörk T (2008) NBS1 variant I171V and breast cancer risk. Breast Cancer Res Treat 112:75–79PubMedCrossRefGoogle Scholar
  30. 30.
    Bogdanova N, Cybulski C, Bermisheva M, Datsyuk I, Yamini P, Hillemanns P, Antonenkova NN, Khusnutdinova E, Lubinski J, Dörk T (2009) A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer. Breast Cancer Res Treat 118(1):207–211PubMedCrossRefGoogle Scholar
  31. 31.
    Bogdanova N, Antonenkova NN, Rogov YI, Karstens JH, Hillemanns P, Dörk T (2010) High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus. Clin Genet 78:364–372PubMedCrossRefGoogle Scholar
  32. 32.
    Ng PC, Henikoff S (2002) Accounting for human polymorphisms predicted to affect protein function. Genome Res 12:436–446PubMedCrossRefGoogle Scholar
  33. 33.
    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249PubMedCrossRefGoogle Scholar
  34. 34.
    D’Andrea AD (2010) Susceptibility pathways in Fanconi’s anemia and breast cancer. New Engl J Med 362:1909–1919PubMedCrossRefGoogle Scholar
  35. 35.
    Levy-Lahad E (2010) Fanconi anemia and breast cancer susceptibility meet again. Nat Genet 42(5):368–369PubMedCrossRefGoogle Scholar
  36. 36.
    Stogios PJ, Downs GS, Jauhal JJS, Nandra SK, Prive GG (2005) Sequence and structural analysis of BTB domain proteins. Genome Biol 8:R82CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Rosa Landwehr
    • 1
  • Natalia V. Bogdanova
    • 1
    • 2
  • Natalia Antonenkova
    • 3
  • Andreas Meyer
    • 2
  • Michael Bremer
    • 2
  • Tjoung-Won Park-Simon
    • 1
  • Peter Hillemanns
    • 1
  • Johann H. Karstens
    • 2
  • Detlev Schindler
    • 4
  • Thilo Dörk
    • 1
  1. 1.Clinics of Obstetrics and GynaecologyHannover Medical SchoolHannoverGermany
  2. 2.Clinics of Radiation OncologyHannover Medical SchoolHannoverGermany
  3. 3.N.N. Alexandrov Research Institute of Oncology and Medical RadiologyMinskBelarus
  4. 4.Institute of Human GeneticsBiocenter, University of WürzburgWürzburgGermany

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