Abstract
BRCA1/2 germline mutations predispose to breast and ovarian cancer. Large genomic rearrangements (LGRs) have widened the mutational spectrum of the BRCA1 gene, but the frequencies vary in different populations. In this study, we want to determine the spectrum of LGRs in BRCA1 gene in Nigerian breast cancer patients. The multiplex ligation-dependent probe amplification (MLPA) assay was used to screen BRCA1 rearrangements in 352 patients who previously tested negative for BRCA1 and BRCA2 point mutations and small insertions/deletions. Positive MLPA result was confirmed and located by long-range PCR. The breakpoints of the candidate rearrangement were characterized by sequencing. A novel deletion of BRCA1 exon 21 (c.5277 + 480_5332 + 672del) was detected in 1 out of 352 Nigerian breast cancer patients (0.3% occurrence frequency). Further analysis of breakpoints revealed that the deletion involves two Alu-elements: one AluSg in intron 20 and the AluY in intron 21. These data suggest that while BRCA1 genomic rearrangement exists, they do not contribute significantly to BRCA1-associated risk in the Nigerian population.
References
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene brca1. Science 266(5182):66–71
Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G (1995) Identification of the breast cancer susceptibility gene brca2. Nature 378(6559):789–792. doi:10.1038/378789a0
King MC, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in brca1 and brca2. Science 302(5645):643–646. doi:10.1126/science.1088759
Unger MA, Nathanson KL, Calzone K, Antin-Ozerkis D, Shih HA, Martin AM, Lenoir GM, Mazoyer S, Weber BL (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(4):841–850
Engert S, Wappenschmidt B, Betz B, Kast K, Kutsche M, Hellebrand H, Goecke TO, Kiechle M, Niederacher D, Schmutzler RK, Meindl A (2008) Mlpa screening in the brca1 gene from 1,506 German hereditary breast cancer cases: novel deletions, frequent involvement of exon 17, and occurrence in single early-onset cases. Hum Mutat 29(7):948–958. doi:10.1002/humu.20723
Lim YK, Lau PT, Ali AB, Lee SC, Wong JE, Putti TC, Sng JH (2007) Identification of novel brca large genomic rearrangements in Singapore Asian breast and ovarian patients with cancer. Clin Genet 71(4):331–342. doi:10.1111/j.1399-0004.2007.00773.x
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(2):168–171. doi:10.1016/j.cancergencyto.2005.12.016
De la Hoya M, Gutierrez-Enriquez S, Velasco E, Osorio A, Sanchez de Abajo A, Vega A, Salazar R, Esteban E, Llort G, Gonzalez-Sarmiento R, Carracedo A, Benitez J, Miner C, Diez O, Diaz-Rubio E, Caldes T (2006) Genomic rearrangements at the brca1 locus in Spanish families with breast/ovarian cancer. Clin Chem 52(8):1480–1485. doi:10.1373/clinchem.2006.070110
Hartmann C, John AL, Klaes R, Hofmann W, Bielen R, Koehler R, Janssen B, Bartram CR, Arnold N, Zschocke J (2004) Large brca1 gene deletions are found in 3% of German high-risk breast cancer families. Hum Mutat 24(6):534. doi:10.1002/humu.9291
Montagna M, Dalla Palma M, Menin C, Agata S, De Nicolo A, Chieco-Bianchi L, D’Andrea E (2003) Genomic rearrangements account for more than one-third of the brca1 mutations in northern Italian breast/ovarian cancer families. Hum Mol Genet 12(9):1055–1061
Moisan AM, Fortin J, Dumont M, Samson C, Bessette P, Chiquette J, Laframboise R, Lepine J, Lesperance B, Pichette R, Plante M, Provencher L, Voyer P, Goldgar D, Bridge P, Simard J (2006) No evidence of brca1/2 genomic rearrangements in high-risk French-Canadian breast/ovarian cancer families. Genet Test 10(2):104–115. doi:10.1089/gte.2006.10.104
Sluiter MD, van Rensburg EJ. Large genomic rearrangements of the brca1 and brca2 genes: review of the literature and report of a novel brca1 mutation. Breast Cancer Res Treat. doi:10.1007/s10549-010-0817-z
Puget N, Torchard D, Serova-Sinilnikova OM, Lynch HT, Feunteun J, Lenoir GM, Mazoyer S (1997) A 1-kb alu-mediated germ-line deletion removing brca1 exon 17. Cancer Res 57(5):828–831
Mazoyer S (2005) Genomic rearrangements in the brca1 and brca2 genes. Hum Mutat 25(5):415–422. doi:10.1002/humu.20169
Palma MD, Domchek SM, Stopfer J, Erlichman J, Siegfried JD, Tigges-Cardwell J, Mason BA, Rebbeck TR, Nathanson KL (2008) The relative contribution of point mutations and genomic rearrangements in brca1 and brca2 in high-risk breast cancer families. Cancer Res 68(17):7006–7014. doi:10.1158/0008-5472.CAN-08-0599
Smith TM, Lee MK, Szabo CI, Jerome N, McEuen M, Taylor M, Hood L, King MC (1996) Complete genomic sequence and analysis of 117 kb of human DNA containing the gene brca1. Genome Res 6(11):1029–1049
Acknowledegments
We would like to thank Dr. Soma Das for providing positive control samples with known BRCA1 rearrangements for MLPA assay. This study was supported by the National Institutes of Health/National Cancer Institute (R01 CA89085-06) and Entertainment Industry Foundation’s National Women Cancer Research Alliance (NWCRA).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, J., Fackenthal, J.D., Huo, D. et al. Searching for large genomic rearrangements of the BRCA1 gene in a Nigerian population. Breast Cancer Res Treat 124, 573–577 (2010). https://doi.org/10.1007/s10549-010-1006-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-010-1006-9