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A common Greenlandic Inuit BRCA1 RING domain founder mutation

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Abstract

Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1 exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn2+ site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight of the families had members with ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all 13 families share a 4.5 Mb genomic fragment containing the BRCA1 gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit, representing almost ~2% of the total Greenlandic Inuit population, showed that the frequency of the mutation was 1.0%. We conclude that the BRCA1 nucleotide 234 T > G is a common Greenlandic Inuit founder mutation. The relative high frequency in the general population, together with the ease of screening and possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented.

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References

  1. Thompson D, Easton D (2004) The genetic epidemiology of breast cancer genes. J Mammary Gland Biol Neoplasia 9(3):221–236. doi:10.1023/B:JOMG.0000048770.90334.3b

    Article  PubMed  Google Scholar 

  2. Jasin M (2002) Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene 21(58):8981–8993. doi:10.1038/sj.onc.1206176

    Article  PubMed  CAS  Google Scholar 

  3. Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108(2):171–182. doi:10.1016/S0092-8674(02)00615-3

    Article  PubMed  CAS  Google Scholar 

  4. Davies AA, Masson JY, McIlwraith MJ, Stasiak AZ, Stasiak A, Venkitaraman AR et al (2001) Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell 7(2):273–282. doi:10.1016/S1097-2765(01)00175-7

    Article  PubMed  CAS  Google Scholar 

  5. Moynahan ME, Pierce AJ, Jasin M (2001) BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 7(2):263–272. doi:10.1016/S1097-2765(01)00174-5

    Article  PubMed  CAS  Google Scholar 

  6. Shin S, Verma IM (2003) BRCA2 cooperates with histone acetyltransferases in androgen receptor-mediated transcription. Proc Natl Acad Sci USA 100(12):7201–7206. doi:10.1073/pnas.1132020100

    Article  PubMed  CAS  Google Scholar 

  7. Marmorstein LY, Kinev AV, Chan GK, Bochar DA, Beniya H, Epstein JA et al (2001) A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression. Cell 104(2):247–257. doi:10.1016/S0092-8674(01)00209-4

    Article  PubMed  CAS  Google Scholar 

  8. Bochar DA, Wang L, Beniya H, Kinev A, Xue Y, Lane WS et al (2000) BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 102(2):257–265. doi:10.1016/S0092-8674(00)00030-1

    Article  PubMed  CAS  Google Scholar 

  9. Morris JR, Solomon E (2004) BRCA1: BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Hum Mol Genet 13(8):807–817. doi:10.1093/hmg/ddh095

    Article  PubMed  CAS  Google Scholar 

  10. Brzovic PS, Meza J, King MC, Klevit RE (1998) The cancer-predisposing mutation C61G disrupts homodimer formation in the NH2-terminal BRCA1 RING finger domain. J Biol Chem 273(14):7795–7799. doi:10.1074/jbc.273.14.7795

    Article  PubMed  CAS  Google Scholar 

  11. Glover JN (2006) Insights into the molecular basis of human hereditary breast cancer from studies of the BRCA1 BRCT domain. Fam Cancer 5(1):89–93. doi:10.1007/s10689-005-2579-z

    Article  PubMed  CAS  Google Scholar 

  12. Glover JN, Williams RS, Lee MS (2004) Interactions between BRCT repeats and phosphoproteins: tangled up in two. Trends Biochem Sci 29(11):579–585. doi:10.1016/j.tibs.2004.09.010

    Article  PubMed  CAS  Google Scholar 

  13. Borden KL, Freemont PS (1996) The RING finger domain: a recent example of a sequence-structure family. Curr Opin Struct Biol 6(3):395–401. doi:10.1016/S0959-440X(96)80060-1

    Article  PubMed  CAS  Google Scholar 

  14. Brzovic RE, Meza PS, King JE, Klevit MC (2001) BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein-protein interactions. J Biol Chem 276(44):41399–41406. doi:10.1074/jbc.M106551200

    Article  PubMed  CAS  Google Scholar 

  15. Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE (2001) Structure of a BRCA1-BARD1 heterodimeric RING-RING complex. Nat Struct Biol 8(10):833–837. doi:10.1038/nsb1001-833

    Article  PubMed  CAS  Google Scholar 

  16. Meza JE, Brzovic PS, King MC, Klevit RE (1999) Mapping the functional domains of BRCA1. Interaction of the ring finger domains of BRCA1 and BARD1. J Biol Chem 274(9):5659–5665. doi:10.1074/jbc.274.9.5659

    Article  PubMed  CAS  Google Scholar 

  17. Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL et al (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 14(4):430–440. doi:10.1038/ng1296-430

    Article  PubMed  CAS  Google Scholar 

  18. Jin Y, Xu XL, Yang MC, Wei F, Ayi TC, Bowcock AM et al (1997) Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains. Proc Natl Acad Sci USA 94(22):12075–12080. doi:10.1073/pnas.94.22.12075

    Article  PubMed  CAS  Google Scholar 

  19. Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J et al (1997) Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90(3):425–435. doi:10.1016/S0092-8674(00)80503-6

    Article  PubMed  CAS  Google Scholar 

  20. Joukov V, Chen J, Fox EA, Green JB, Livingston DM (2001) Functional communication between endogenous BRCA1 and its partner, BARD1, during Xenopus laevis development. Proc Natl Acad Sci USA 98(21):12078–12083. doi:10.1073/pnas.211427098

    Article  PubMed  CAS  Google Scholar 

  21. Chen A, Kleiman FE, Manley JL, Ouchi T, Pan ZQ (2002) Autoubiquitination of the BRCA1*BARD1 RING ubiquitin ligase. J Biol Chem 277(24):22085–22092. doi:10.1074/jbc.M201252200

    Article  PubMed  CAS  Google Scholar 

  22. Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D, Yabuki Y et al (2001) The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J Biol Chem 276(18):14537–14540. doi:10.1074/jbc.C000881200

    Article  PubMed  CAS  Google Scholar 

  23. Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM (1999) RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci USA 96(20):11364–11369. doi:10.1073/pnas.96.20.11364

    Article  PubMed  CAS  Google Scholar 

  24. Ruffner H, Joazeiro CA, Hemmati D, Hunter T, Verma IM (2001) Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci USA 98(9):5134–5139. doi:10.1073/pnas.081068398

    Article  PubMed  CAS  Google Scholar 

  25. Kim H, Chen J, Yu X (2007) Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316(5828):1202–1205. doi:10.1126/science.1139621

    Article  PubMed  CAS  Google Scholar 

  26. Liu Z, Wu J, Yu X (2007) CCDC98 targets BRCA1 to DNA damage sites. Nat Struct Mol Biol 14(8):716–720. doi:10.1038/nsmb1279

    Article  PubMed  CAS  Google Scholar 

  27. Sobhian B, Shao G, Lilli DR, Culhane AC, Moreau LA, Xia B et al (2007) RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316(5828):1198–1202. doi:10.1126/science.1139516

    Article  PubMed  CAS  Google Scholar 

  28. Wang B, Elledge SJ (2007) Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc Natl Acad Sci USA 104(52):20759–20763. doi:10.1073/pnas.0710061104

    Article  PubMed  CAS  Google Scholar 

  29. Wang B, Matsuoka S, Ballif BA, Zhang D, Smogorzewska A, Gygi SP et al (2007) Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316(5828):1194–1198. doi:10.1126/science.1139476

    Article  PubMed  CAS  Google Scholar 

  30. Eakin CM, Maccoss MJ, Finney GL, Klevit RE (2007) Estrogen receptor alpha is a putative substrate for the BRCA1 ubiquitin ligase. Proc Natl Acad Sci USA 104(14):5794–5799. doi:10.1073/pnas.0610887104

    Article  PubMed  CAS  Google Scholar 

  31. Mallery DL, Vandenberg CJ, Hiom K (2002) Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. EMBO J 21(24):6755–6762. doi:10.1093/emboj/cdf691

    Article  PubMed  CAS  Google Scholar 

  32. Starita LM, Horwitz AA, Keogh MC, Ishioka C, Parvin JD, Chiba N (2005) BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II. J Biol Chem 280(26):24498–24505. doi:10.1074/jbc.M414020200

    Article  PubMed  CAS  Google Scholar 

  33. Starita LM, Machida Y, Sankaran S, Elias JE, Griffin K, Schlegel BP et al (2004) BRCA1-dependent ubiquitination of gamma-tubulin regulates centrosome number. Mol Cell Biol 24(19):8457–8466. doi:10.1128/MCB.24.19.8457-8466.2004

    Article  PubMed  CAS  Google Scholar 

  34. Wu W, Nishikawa H, Hayami R, Sato K, Honda A, Aratani S et al (2007) BRCA1 ubiquitinates RPB8 in response to DNA damage. Cancer Res 67(3):951–958. doi:10.1158/0008-5472.CAN-06-3187

    Article  PubMed  CAS  Google Scholar 

  35. Yu X, Fu S, Lai M, Baer R, Chen J (2006) BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev 20(13):1721–1726. doi:10.1101/gad.1431006

    Article  PubMed  CAS  Google Scholar 

  36. Morris JR, Pangon L, Boutell C, Katagiri T, Keep NH, Solomon E (2006) Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility. Hum Mol Genet 15(4):599–606. doi:10.1093/hmg/ddi476

    Article  PubMed  CAS  Google Scholar 

  37. Bjerregaard P, Curtis T, Borch-Johnsen K, Mulvad G, Becker U, Andersen S et al (2003) Inuit health in Greenland: a population survey of life style and disease in Greenland and among Inuit living in Denmark. Int J Circumpolar Health 62(Suppl 1):3–79

    PubMed  Google Scholar 

  38. Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68(4):820–823. doi:10.1073/pnas.68.4.820

    Article  PubMed  Google Scholar 

  39. Friborg J, Koch A, Wohlfarht J, Storm HH, Melbye M (2003) Cancer in Greenlandic Inuit 1973–1997: a cohort study. Int J Cancer 107(6):1017–1022. doi:10.1002/ijc.11502

    Article  PubMed  CAS  Google Scholar 

  40. Abkevich V, Zharkikh A, Deffenbaugh AM, Frank D, Chen Y, Shattuck D et al (2004) Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet 41(7):492–507. doi:10.1136/jmg.2003.015867

    Article  PubMed  CAS  Google Scholar 

  41. Brzovic PS, Keeffe JR, Nishikawa H, Miyamoto K, Fox D 3rd, Fukuda M et al (2003) Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex. Proc Natl Acad Sci USA 100(10):5646–5651. doi:10.1073/pnas.0836054100

    Article  PubMed  CAS  Google Scholar 

  42. Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington PA, Chiano M et al (1995) Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet 11(4):428–433. doi:10.1038/ng1295-428

    Article  PubMed  CAS  Google Scholar 

  43. Holt JT, Thompson ME, Szabo C, Robinson-Benion C, Arteaga CL, King MC et al (1996) Growth retardation and tumour inhibition by BRCA1. Nat Genet 12(3):298–302. doi:10.1038/ng0396-298

    Article  PubMed  CAS  Google Scholar 

  44. Thompson D, Easton D (2002) Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev 11(4):329–336

    PubMed  CAS  Google Scholar 

  45. Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA et al (1997) Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15(1):103–105. doi:10.1038/ng0197-103

    Article  PubMed  CAS  Google Scholar 

  46. Bergman A, Einbeigi Z, Olofsson U, Taib Z, Wallgren A, Karlsson P et al (2001) The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation. Eur J Hum Genet 9(10):787–793. doi:10.1038/sj.ejhg.5200704

    Article  PubMed  CAS  Google Scholar 

  47. Dorum A, Hovig E, Trope C, Inganas M, Moller P (1999) Three per cent of Norwegian ovarian cancers are caused by BRCA1 1675delA or 1135insA. Eur J Cancer 35(5):779–781. doi:10.1016/S0959-8049(99)00050-7

    Article  PubMed  CAS  Google Scholar 

  48. Simard J, Tonin P, Durocher F, Morgan K, Rommens J, Gingras S et al (1994) Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet 8(4):392–398. doi:10.1038/ng1294-392

    Article  PubMed  CAS  Google Scholar 

  49. Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV et al (1996) A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13(1):117–119. doi:10.1038/ng0596-117

    Article  PubMed  CAS  Google Scholar 

  50. Helgason A, Palsson G, Pedersen HS, Angulalik E, Gunnarsdottir ED, Yngvadottir B et al (2006) mtDNA variation in Inuit populations of Greenland and Canada: migration history and population structure. Am J Phys Anthropol 130(1):123–134. doi:10.1002/ajpa.20313

    Article  PubMed  Google Scholar 

  51. Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L et al (1997) Study of a single BRCA2 mutation with high carrier frequency in a small population. Am J Hum Genet 60(5):1079–1084

    PubMed  CAS  Google Scholar 

  52. Roa BB, Boyd AA, Volcik K, Richards CS (1996) Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14(2):185–187. doi:10.1038/ng1096-185

    Article  PubMed  CAS  Google Scholar 

  53. Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, Collins FS et al (1995) The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11(2):198–200. doi:10.1038/ng1095-198

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Nina Ilsøe, Bettina M. Andersen, Karina Nørgaard and Lis Krüger are acknowledged for excellent technical assistance. This study was supported by the Neye Foundation.

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Authors and Affiliations

  1. Department of Clinical Biochemistry 4111, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Thomas v. O. Hansen, Peter B. Nielsen, Lars Jønson & Finn C. Nielsen

  2. Department of Oncology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Bent Ejlertsen & Eva Bergsten

  3. Department of Biostatistics, University of Copenhagen, Øster Farimagsgade 5, 1014, Copenhagen, Denmark

    Anders Albrechtsen

  4. National Institute of Public Health, Øster Farimagsgade 5, 1399, Copenhagen, Denmark

    Peter Bjerregaard

  5. Steno Diabetes Center, Niels Steensens Vej 2, 2820, Gentofte, Denmark

    Torben Hansen

  6. Department of Surgery, Dronning Ingrids Hospital, Postbox 3333, 3900, Nuuk, Greenland

    Torben Myrhøj

  7. Department of Pathology, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Vera Timmermans-Wielenga

  8. Department of Clinical Genetics, Juliane Marie Center, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Mette K. Andersen

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  1. Thomas v. O. Hansen
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Correspondence to Thomas v. O. Hansen.

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Hansen, T.v.O., Ejlertsen, B., Albrechtsen, A. et al. A common Greenlandic Inuit BRCA1 RING domain founder mutation. Breast Cancer Res Treat 115, 69–76 (2009). https://doi.org/10.1007/s10549-008-0060-z

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