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01-05-2009 | Preclinical Study

Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families

Authors: Thomas v. O. Hansen, Lars Jønson, Anders Albrechtsen, Mette K. Andersen, Bent Ejlertsen, Finn C. Nielsen

Published in: Breast Cancer Research and Treatment | Issue 2/2009

Abstract

BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0–36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian cancer patients in whom a deleterious mutation in BRCA1 and BRCA2 was not detected by sequencing using the multiplex ligation-dependent probe amplification (MLPA) assay. We identified 15 patients with 7 different genomic rearrangements, including a BRCA1 exon 5–7 deletion with a novel breakpoint, a BRCA1 exon 13 duplication, a BRCA1 exon 17–19 deletion, a BRCA1 exon 3–16 deletion, and a BRCA2 exon 20 deletion with a novel breakpoint as well as two novel BRCA1 exon 17–18 and BRCA1 exon 19 deletions. The large rearrangements in BRCA1 and BRCA2 accounted for 9.2% (15/163) of all BRCA1 and BRCA2 mutations in East Denmark. Nine patients had the exon 3–16 deletion in BRCA1. By SNP analysis we find that the patients share a 5 Mb fragment of chromosome 17, including BRCA1, indicating that the exon 3–16 deletion represents a Danish founder mutation.

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

Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B et al (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684–1689. doi:10.1126/science.2270482 PubMedCrossRef

Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71. doi:10.1126/science.7545954 PubMedCrossRef

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 14:430–440. doi:10.1038/ng1296-430 PubMedCrossRef

Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S et al (2001) BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105:149–160. doi:10.1016/S0092-8674(01)00304-X PubMedCrossRef

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 316:1194–1198. doi:10.1126/science.1139476 PubMedCrossRef

Yu X, Wu LC, Bowcock AM, Aronheim A, Baer R (1998) The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J Biol Chem 273:25388–25392. doi:10.1074/jbc.273.39.25388 PubMedCrossRef

Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N et al (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265:2088–2090. doi:10.1126/science.8091231 PubMedCrossRef

Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792. doi:10.1038/378789a0 PubMedCrossRef

10.

Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E, Dinh C et al (1997) Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking BRCA2. Nature 386:804–810. doi:10.1038/386804a0 PubMedCrossRef

11.

Wong AK, Pero R, Ormonde PA, Tavtigian SV, Bartel PL (1997) RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene BRCA2. J Biol Chem 272:31941–31944. doi:10.1074/jbc.272.51.31941 PubMedCrossRef

12.

Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW et al (1999) Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 3:389–395. doi:10.1016/S1097-2765(00)80466-9 PubMedCrossRef

13.

Yu VP, Koehler M, Steinlein C, Schmid M, Hanakahi LA, van Gool AJ et al (2000) Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev 14:1400–1406PubMed

14.

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 7:273–282. doi:10.1016/S1097-2765(01)00175-7 PubMedCrossRef

15.

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

16.

Shin S, Verma IM (2001) BRCA2 cooperates with histone acetyltransferases in androgen receptor-mediated transcription. Proc Natl Acad Sci USA 2003 100(12):7201–7206CrossRef

17.

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 104:247–257. doi:10.1016/S0092-8674(01)00209-4

18.

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 102:257–265. doi:10.1016/S0092-8674(00)00030-1 PubMedCrossRef

19.

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 13:807–817. doi:10.1093/hmg/ddh095 PubMedCrossRef

20.

Puget N, Torchard D, Serova-Sinilnikova OM, Lynch HT, Feunteun J, Lenoir GM et al (1997) A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res 57:828–831PubMed

21.

Puget N, Sinilnikova OM, Stoppa-Lyonnet D, Audoynaud C, Pages S, Lynch HT et al (1999) An Alu-mediated 6-kb duplication in the BRCA1 gene: a new founder mutation? Am J Hum Genet 64:300–302. doi:10.1086/302211 PubMedCrossRef

22.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. doi:10.1086/519795 PubMedCrossRef

23.

Hogervorst FB, Nederlof PM, Gille JJ, McElgunn CJ, Grippeling M, Pruntel R et al (2003) Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method. Cancer Res 63:1449–1453PubMed

24.

Thomassen M, Gerdes AM, Cruger D, Jensen PK, Kruse TA (2006) Low frequency of large genomic rearrangements of BRCA1 and BRCA2 in western Denmark. Cancer Genet Cytogenet 168:168–171. doi:10.1016/j.cancergencyto.2005.12.016 PubMedCrossRef

25.

Lahti-Domenici J, Rapakko K, Paakkonen K, Allinen M, Nevanlinna H, Kujala M et al (2001) Exclusion of large deletions and other rearrangements in BRCA1 and BRCA2 in Finnish breast and ovarian cancer families. Cancer Genet Cytogenet 129:120–123. doi:10.1016/S0165-4608(01)00437-X PubMedCrossRef

26.

Moisan AM, Fortin J, Dumont M, Samson C, Bessette P, Chiquette J et al (2006) No evidence of BRCA1/2 genomic rearrangements in high-risk French-Canadian breast/ovarian cancer families. Genet Test 10:104–115. doi:10.1089/gte.2006.10.104 PubMedCrossRef

27.

Gad S, Caux-Moncoutier V, Pages-Berhouet S, Gauthier-Villars M, Coupier I, Pujol P et al (2002) Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families. Oncogene 21:6841–6847. doi:10.1038/sj.onc.1205685 PubMedCrossRef

28.

de la Hoya M, Gutierrez-Enriquez S, Velasco E, Osorio A, Sanchez de Abajo A, Vega A et al (2006) Genomic rearrangements at the BRCA1 locus in Spanish families with breast/ovarian cancer. Clin Chem 52:1480–1485. doi:10.1373/clinchem.2006.070110 PubMedCrossRef

29.

Hartmann C, John AL, Klaes R, Hofmann W, Bielen R, Koehler R et al (2004) Large BRCA1 gene deletions are found in 3% of German high-risk breast cancer families. Hum Mutat 24:534. doi:10.1002/humu.9291 PubMedCrossRef

30.

Vasickova P, Machackova E, Lukesova M, Damborsky J, Horky O, Pavlu H et al (2007) High occurrence of BRCA1 intragenic rearrangements in hereditary breast and ovarian cancer syndrome in the Czech Republic. BMC Med Genet 8:32. doi:10.1186/1471-2350-8-32 PubMedCrossRef

31.

Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drusedau M et al (1997) BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 17:341–345. doi:10.1038/ng1197-341 PubMedCrossRef

32.

Agata S, Viel A, Della Puppa L, Cortesi L, Fersini G, Callegaro M et al (2006) Prevalence of BRCA1 genomic rearrangements in a large cohort of Italian breast and breast/ovarian cancer families without detectable BRCA1 and BRCA2 point mutations. Genes Chromosomes Cancer 45:791–797. doi:10.1002/gcc.20342 PubMedCrossRef

33.

Gad S, Klinger M, Caux-Moncoutier V, Pages-Berhouet S, Gauthier-Villars M, Coupier I et al (2002) Bar code screening on combed DNA for large rearrangements of the BRCA1 and BRCA2 genes in French breast cancer families. J Med Genet 39:817–821. doi:10.1136/jmg.39.11.817 PubMedCrossRef

34.

Peelen T, van Vliet M, Bosch A, Bignell G, Vasen HF, Klijn JG et al (2000) Screening for BRCA2 mutations in 81 Dutch breast-ovarian cancer families. Br J Cancer 82:151–156. doi:10.1054/bjoc.1999.0892 PubMedCrossRef

35.

Tournier I, Paillerets BB, Sobol H, Stoppa-Lyonnet D, Lidereau R, Barrois M et al (2004) Significant contribution of germline BRCA2 rearrangements in male breast cancer families. Cancer Res 64:8143–8147. doi:10.1158/0008-5472.CAN-04-2467 PubMedCrossRef

36.

Woodward AM, Davis TA, Silva AG, Kirk JA, Leary JA (2005) Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families. J Med Genet 42:e31. doi:10.1136/jmg.2004.027961 PubMedCrossRef

37.

Couch FJ, DeShano ML, Blackwood MA, Calzone K, Stopfer J, Campeau L et al (1997) BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336:1409–1415. doi:10.1056/NEJM199705153362002 PubMedCrossRef

38.

Ramus SJ, Harrington PA, Pye C, DiCioccio RA, Cox MJ, Garlinghouse-Jones K et al (2007) Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum Mutat 28:1207–1215. doi:10.1002/humu.20599 PubMedCrossRef

39.

Preisler-Adams S, Schonbuchner I, Fiebig B, Welling B, Dworniczak B, Weber BH (2006) Gross rearrangements in BRCA1 but not BRCA2 play a notable role in predisposition to breast and ovarian cancer in high-risk families of German origin. Cancer Genet Cytogenet 168:44–49. doi:10.1016/j.cancergencyto.2005.07.005 PubMedCrossRef

40.

Kremeyer B, Soller M, Lagerstedt K, Maguire P, Mazoyer S, Nordling M et al (2005) The BRCA1 exon 13 duplication in the Swedish population. Fam Cancer 4:191–194. doi:10.1007/s10689-004-7023-2 PubMedCrossRef

41.

Lim YK, Lau PT, Ali AB, Lee SC, Wong JE, Putti TC et al (2007) Identification of novel BRCA large genomic rearrangements in Singapore Asian breast and ovarian patients with cancer. Clin Genet 71:331–342. doi:10.1111/j.1399-0004.2007.00773.x PubMedCrossRef

42.

Unger MA, Nathanson KL, Calzone K, Antin-Ozerkis D, Shih HA, Martin AM et al (2000) Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Genet 67:841–850. doi:10.1086/303076 PubMedCrossRef

43.

Agata S, Dalla Palma M, Callegaro M, Scaini MC, Menin C, Ghiotto C et al (2005) Large genomic deletions inactivate the BRCA2 gene in breast cancer families. J Med Genet 42:e64. doi:10.1136/jmg.2005.032789 PubMedCrossRef

Title: Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families
Authors: Thomas v. O. Hansen
Lars Jønson
Anders Albrechtsen
Mette K. Andersen
Bent Ejlertsen
Finn C. Nielsen
Publication date: 01-05-2009
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2009
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-008-0088-0

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