Abstract
Background Alterations in BRCA1 gene are responsible for the majority of hereditary breast and/or ovarian cancers. However, the frequency of detected germline mutations is lower than expected by linkage analysis. Standard PCR-based screening methods are mainly used for detecting mutations, but the large genomic rearrangements are commonly overlooked. The purpose of this study was to confirm and characterize a novel deletion identified in BRCA1 gene which has not yet been reported to date. Methods Multiplex ligation-dependent probe amplification was used to analyze BRCA1 rearrangements in 255 unrelated index patients with familial breast and/or ovarian cancer negative for BRCA1/BRCA2 mutations studied in Program of Genetic Counselling on Cancer of Valencia Community (Spain). The breakpoints of detected novel rearrangement were characterized by sequencing. Results and discussion Five different rearrangements in the BRCA1 gene were identified in five unrelated index patients out of the 225 (2%). We found four large genomic rearrangements already described consisting in a 1A/1B and 2 deletion; deletion of exons 5–7; deletion of exons 8–13; exon 20 deletion. Additionally, we found the novel g.8097_22733del14637 deletion that encompasses exons 3–5. This deletion affects the RING domain of the BRCA1 protein and it is suggestive of having a negative impact on its function. Conclusion The new mutation here reported broadens the mutational spectrum of large rearrangements. Furthermore, the five large rearrangements found in patients non-carriers of BRCA1/BRCA2 mutations reinforce the need of studying BRCA1 large genomic rearrangements in genetic counselling programs.
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References
Ford D, Easton DF, Stratton M et al (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 62:676–689
Szabo CI, King MC (1997) Population genetics of BRCA1 and BRCA2. Am J Hum Genet 60:1013–1020
Puget N, Gad S, Perrin-Vidoz L et al (2002) Distinct BRCA1 rearrangements involving the BRCA1 pseudogene suggest the existence of a recombination hot spot. Am J Hum Genet 70:858–865
Brown MA, Lo LJ, Catteau A et al (2002) Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients: identification of a novel deletion consistent with BRCA1:ψ BRCA1 recombination. Hum Mutat 19:435–442
Woodward AM, Davis TA, Silva AG et al (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
Mazoyer S (2005) Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat 25:415–422
Montagna M, Dalla Palma M, Menin C et al (2003) Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum Mol Genet 12:1055–1061
Petrij-Bosch A, Peelen T, van Vliet M et al (1997) BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 17:341–345
Gad S, Klinger M, Caux-Moncoutier V 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
Hofmann W, Gorgens H, John A et al (2003) Screening for large rearrangements of the BRCA1 gene in German breast or ovarian cancer families using semi-quantitative multiplex PCR method. Hum Mutat 22:103–104
Belogianni I, Apessos A, Mihalatos M et al (2004) Characterization of a novel large deletion and single point mutations in the BRCA1 gene in a Greek cohort of families with suspected hereditary breast cancer. BMC Cancer 4:61
Lahti-Domenici J, Rapakko K, Pääkkönen K 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
de la Hoya M, Gutiérrez-Enríquez S, Velasco E et al (2006) Genomic rearrangements at the BRCA1 locus in Spanish families with breast/ovarian cancer. Clin Chem 52:1480–1485
Programa de Consejo Genético en el Cáncer. Grupo de Cáncer Hereditario (2003) Plan Oncológico. Comunidad Valenciana. Conselleria de Sanitat, Valencia
The Breast Cancer Information Core Database, BIC. http://research.nhgri.nih.gov/bic/Member/index.shtml
Ganguly A, Rock MJ, Prockop DJ (1993) Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proc Natl Acad Sci USA 90:10325–10329
Cardeñosa E, Bolufer P, Palanca S et al BRCA1 and BRCA2 mutations in families studied in the program of genetic counselling in cancer of the Valencia Community. Med Clin (Barn), in press
Schouten JP, McElgunn CJ, Waaijer R et al (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30:e57
Expasy Proteomic: http://www.expasy.org/tools/
Repeat Masker program: http://www.repeatmasker.org/
Swensen J, Hoffman M, Skolnick MH et al (1997) Identification of a 14 kb deletion involving the promoter region of BRCA1 in a breast cancer family. Hum Mol Genet 6:1513–1517
Preisler-Adams S, Schonbuchner I, Fiebig B et al (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
Puget N, Stoppa-Lyonnet D, Sinilnikova OM et al (1999) Screening for germ-line rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions. Cancer Res 59:455–461
Carson N, Gilpin C, Hunter A et al (1999) An in frame deletion of BRCA1 exon 20 in a family with early onset breast and ovarian cancer. Am J Hum Genet 65:A1610
Rohlfs EM, Chung CH, Yang Q et al (2000) In-frame deletions of BRCA1 may define critical functional domains. Hum Genet 107:385–390
Rudiger NS, Gregersen N, Kielland-Brandt MC (1995) One short well conserved region of Alu-sequences is involved in human gene rearrangements and has homology with prokaryotic chi. Nucleic Acids Res 23:256–260
Acknowledgements
We should manifest our gratitude to the “Fundación para Investigación La Fe” for having granted Sarai Palanca Suela (Lda. in Farmacy and Specialist in Clinical Biopathology) in a research project in HBC, which made possible her participation in the present study. Gratefully acknowledge support for the development of research projects in field of health to the “Consellería de Sanitat” from Valencia Community (project AP-019/06). We also should express our gratitude to Dr. Dolores Cuevas Cuerda (Jefa de Servicio de Protocolización e Integración Asistencial, Dirección de Asistencia Sanitaria, Consellería de Sanitat, Generalitat Valenciana) and Dolores Salas Trejo (Jefa de Servicio de la Oficina del Plan de Cáncer, Dirección General de Salud Pública, Consellería de Sanitat, Generalitat Valenciana) for her help and strong support given to establish and develop the Program of Genetic Counselling in Cancer of Valencia Community.
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Palanca Suela, S., Esteban Cardeñosa, E., Barragán González, E. et al. Identification of a novel BRCA1 large genomic rearrangement in a Spanish breast/ovarian cancer family. Breast Cancer Res Treat 112, 63–67 (2008). https://doi.org/10.1007/s10549-007-9839-6
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DOI: https://doi.org/10.1007/s10549-007-9839-6