Skip to main content

Advertisement

SpringerLink
Log in

A high frequent BRCA1 founder mutation identified in the Greenlandic population

  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Approximately 10% of all breast and ovarian cancers are dominantly inherited and mutations are mainly found in the BRCA 1 and 2 genes. The penetrance of BRCA1 mutations is reported to be between 68 and 92% and confers a 36–92% life time risk of breast cancer. Most mutations in BRCA1 are uniquely occurring mutations, but founder mutations have been described. In this study we describe a founder mutation with wide spread presence in the Inuit population. We have screened 2,869 persons from Greenland for the presence of a BRCA1 mutation (p.Cys39Gly) only found in the Inuit population. The overall carrier frequency was 1.6% in the general population, but the frequency differs geographically from 0.6% on the West coast to 9.7% in the previously isolated population of the East coast. This is to our knowledge the highest population frequency of a BRCA1 mutation ever to be described. To determine the clinical relevance of the mutation, we have examined ten breast cancer patients and nine ovarian cancer patients from Greenland for the presence of the p.Cys39Gly mutation. We found three ovarian cancer patients (33%) and one breast cancer patient (10%) carrying the mutation. The high number of women carrying a BRCA1 mutation known to trigger the development of potentially lethal diseases leads us to recommend an offer of genetic counselling and test for the mutation to all females of Inuit origin, thereby hopefully preventing a number of breast and ovarian cancer deaths.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 2:74–108. doi:10.3322/canjclin.55.2.74

    Article  Google Scholar 

  2. Claus EB, Schildkraut JM, Thompson WD, Risch NJ (1996) The genetic attributable risk of breast and ovarian cancer. Cancer 11:2318–2324. doi:10.1002/(SICI)1097-0142(19960601)77:11<2318::AID-CNCR21>3.0.CO;2-Z

    Article  Google Scholar 

  3. McPherson K, Steel CM, Dixon JM (2000) ABC of breast diseases. Breast cancer-epidemiology, risk factors, and genetics. BMJ 7261:624–628. doi:10.1136/bmj.321.7261.624

    Article  Google Scholar 

  4. Fodor FH, Weston A, Bleiweiss IJ, McCurdy LD, Walsh MM, Tartter PI, Brower ST, Eng CM (1998) Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am J Hum Genet 1:45–51. doi:10.1086/301903

    Article  Google Scholar 

  5. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 3:676–689. doi:10.1086/301749

    Article  Google Scholar 

  6. King MC, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 5645:643–646. doi:10.1126/science.1088759

    Article  CAS  Google Scholar 

  7. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA (1997) The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 20:1401–1408. doi:10.1056/NEJM199705153362001

    Article  Google Scholar 

  8. McClain MR, Nathanson KL, Palomaki GE, Haddow JE (2005) An evaluation of BRCA1 and BRCA2 founder mutations penetrance estimates for breast cancer among Ashkenazi Jewish women. Genet Med 1:34–39. doi:10.1097/01.GIM.0000151156.14983.08

    Article  Google Scholar 

  9. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, Jack E, Vesprini DJ, Kuperstein G, Abrahamson JL, Fan I, Wong B, Narod SA (2001) Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 3:700–710. doi:10.1086/318787

    Article  Google Scholar 

  10. Palomba G, Cossu A, Friedman E, Budroni M, Farris A, Contu A, Pisano M, Baldinu P, Sini MC, Tanda F, Palmieri G (2007) Origin and distribution of the BRCA2–8765delAG mutation in breast cancer. BMC Cancer 7:132. doi:10.1186/1471-2407-7-132

    Article  PubMed  CAS  Google Scholar 

  11. Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, Gumpper KL, Scholl T, Tavtigian SV, Pruss DR, Critchfield GC (2002) Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 6:1480–1490. doi:10.1200/JCO.20.6.1480

    Article  Google Scholar 

  12. Eiberg H, Norgaard-Pedersen B, Nielsen IM (2004) Cholestasis Familiaris Groenlandica/Byler-like disease in Greenland—a population study. Int J Circumpolar Health 63(Suppl 2):189–191

    PubMed  Google Scholar 

  13. Ravn K, Chloupkova M, Christensen E, Brandt NJ, Simonsen H, Kraus JP, Nielsen IM, Skovby F, Schwartz M (2000) High incidence of propionic acidemia in Greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase. Am J Hum Genet 1:203–206. doi:10.1086/302971

    Article  Google Scholar 

  14. Walsh PS, Metzger DA, Higuchi R (1991) Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. Biotechniques 4:506–513

    Google Scholar 

  15. Grantham R (1974) Amino acid difference formula to help explain protein evolution. Science 4154:862–864. doi:10.1126/science.185.4154.862

    Article  Google Scholar 

  16. Mathe E, Olivier M, Kato S, Ishioka C, Hainaut P, Tavtigian SV (2006) Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods. Nucleic Acids Res 5:1317–1325. doi:10.1093/nar/gkj518

    Article  CAS  Google Scholar 

  17. Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 17:3894–3900. doi:10.1093/nar/gkf493

    Article  Google Scholar 

  18. Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 13:3812–3814. doi:10.1093/nar/gkg509

    Article  Google Scholar 

  19. Hansen TV, Ejlertsen B, Albrechtsen A, Bergsten E, Bjerregaard P, Hansen T, Myrhoj T, Nielsen PB, Timmermans-Wielenga V, Andersen MK, Jonson L, Nielsen FC (2008) A common Greenlandic Inuit BRCA1 RING domain founder mutation. Breast Cancer Res Treat 115(11):69–76

    PubMed  Google Scholar 

  20. Bisgaard ML, Harboe TL, Ejlertsen B, Nielsen IM, and Eiberg H (2007) Hereditary disposition to cancer of the breast and ovary in the Eastgreenlandic population. Nuna Med conference 2007 (http://www.nunamed.org/Dokumenter/Abstracts%20tekst.pdf)

  21. Thomassen M, Hansen TV, Borg A, Lianee HT, Wikman F, Pedersen IS, Bisgaard ML, Nielsen FC, Kruse TA, Gerdes AM (2008) BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer. Acta Oncol 4:772–777. doi:10.1080/02841860802004974

    Article  CAS  Google Scholar 

  22. 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 14:7795–7799. doi:10.1074/jbc.273.14.7795

    Article  Google Scholar 

  23. Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL, Yang MC, Hwang LY, Bowcock AM, Baer R (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 4:430–440. doi:10.1038/ng1296-430

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  26. Haitian Z, Yunfei L, Jian Z, Jian L, Qinghua L, Fuqiang W (2008) Mutation screening of the BRCA1 gene in sporadic breast cancer in southern Chinese populations. Breast 6:563–567. doi:10.1016/j.breast.2008.08.003

    Article  Google Scholar 

  27. Merajver SD, Pham TM, Caduff RF, Chen M, Poy EL, Cooney KA, Weber BL, Collins FS, Johnston C, Frank TS (1995) Somatic mutations in the BRCA1 gene in sporadic ovarian tumours. Nat Genet 4:439–443. doi:10.1038/ng0495-439

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Boysen T, Friborg J, Andersen A, Poulsen GN, Wohlfahrt J, Melbye M (2008) The Inuit cancer pattern—the influence of migration. Int J Cancer 11:2568–2572. doi:10.1002/ijc.23367

    Article  CAS  Google Scholar 

  30. Narod SA (2006) Modifiers of risk of hereditary breast cancer. Oncogene 43:5832–5836. doi:10.1038/sj.onc.1209870

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  33. Johannesdottir G, Gudmundsson J, Bergthorsson JT, Arason A, Agnarsson BA, Eiriksdottir G, Johannsson OT, Borg A, Ingvarsson S, Easton DF, Egilsson V, Barkardottir RB (1996) High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients. Cancer Res 16:3663–3665

    Google Scholar 

  34. Rafnar T, Benediktsdottir KR, Eldon BJ, Gestsson T, Saemundsson H, Olafsson K, Salvarsdottir A, Steingrimsson E, Thorlacius S (2004) BRCA2, but not BRCA1, mutations account for familial ovarian cancer in Iceland: a population-based study. Eur J Cancer 18:2788–2793. doi:10.1016/j.ejca.2004.09.008

    Article  CAS  Google Scholar 

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

    Google Scholar 

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

    Article  Google Scholar 

  37. Gulløv HC (ed) (2004) Grønlands forhistorie. Gyldendal, Copenhagen, Denmark

Download references

Acknowledgments

The authors would like to thank Tina Wandall, Gitte Kristensen, Theresa Wass and Karina Thaysen for their excellent laboratory assistance. This study was supported by the following foundations: Olga og Espen Boels Fond, Fabrikant Einar Willumsens Mindelegat, Kong Christian den Tiendens Fond, Civilingenør Bent Bøgh og Hustru Inge Bøgh’s Fond, Victoria og Henry Andersens legat, Meta og Håkon Baggers Fond and Grosserer Valdemar Foerson og Hustru Thyra Foersom, født Ottos Fond and Arvid Nilssons Fond. TLH was generously supported with a senior research scholarship from Fonden af 17-12-1981. This study has been approved by the Danish Research Ethics Committees and The Commission for Scientific Research in Greenland.

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Building 24.4.52, Blegdamsvej 3, 2200, Copenhagen N, Denmark

    Theresa Larriba Harboe, Hans Eiberg, Inge-Merete Nielsen & Marie Luise Bisgaard

  2. Department of Gynecology and Obstetrics, Queen Ingrid’s Hospital, Nuuk, Greenland

    Peder Kern

  3. Department of Oncology, Rigshospitalet, 5012, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark

    Bent Ejlertsen

  4. Department of Pathology, Rigshospitalet, 5441, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark

    Lotte Nedergaard & Vera Timmermans-Wielenga

Authors
  1. Theresa Larriba Harboe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans Eiberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peder Kern
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bent Ejlertsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lotte Nedergaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vera Timmermans-Wielenga
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Inge-Merete Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marie Luise Bisgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theresa Larriba Harboe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harboe, T.L., Eiberg, H., Kern, P. et al. A high frequent BRCA1 founder mutation identified in the Greenlandic population. Familial Cancer 8, 413–419 (2009). https://doi.org/10.1007/s10689-009-9257-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-009-9257-5

Keywords

Search

Navigation