HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: clinchem.2006.070110v1 52/8/1480    most recent Submit an electronic Letter to the Editor about this paper Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by de la Hoya, M. Articles by Caldes, T. Search for Related Content PubMed PubMed Citation Articles by de la Hoya, M. Articles by Caldes, T. Related Collections Molecular Diagnostics and Genetics

Genomic Rearrangements at the BRCA1 Locus in Spanish Families with Breast/Ovarian Cancer

¹ Laboratorio de Oncología Molecular y Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain.
² Servei de Genética, Hospital de la Santa Creu iSant Pau, Barcelona, Spain.
³ Instituto de Biología y Genética Molecular, Facultad de Medicina, Universidad de Valladolid, Valladolid, Spain.
⁴ Departmento de Genética Humana, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
⁵ Unidad de Medicina Molecular, Fundación Pública Galega de Medicina Xenómica, (FPGMX), Hospital Clínico Universitario, Santiago de Compostela, Spain.
⁶ Centro de Investigación del Cáncer-Universidad de Salamanca, Salamanca, Spain.
⁷ Unidad de Consejo Genético, Servicio de Prevención y Control del Cáncer, Institut Català d’Oncologia, Barcelona, Spain.
⁸ Unidad de Xenética, Instituto de Medicina Legal, Facultad de Medicina, Universidad de Santiago de Compostela, Galicia, Spain.

^aAddress correspondence to this author at: Laboratorio de Oncología Molecular, Hospital Clínico San Carlos, C/Martín Lagos s/n, 28040 Madrid, Spain. Fax 34-91-330-3544; E-mail tcaldes.hcsc{at}salud.madrid.org.

Background: Large genomic rearrangements (LGRs) account for a substantial proportion of the BRCA1 disease-causing changes, or variations, identified in families with hereditary breast/ovarian cancer [HB(O)C]. Great differences in the spectrum and prevalence of BRCA1 LGR have been observed among populations. Here we report the first comprehensive analysis of BRCA1 LGRs conducted in Spain.

Methods: We used multiplex ligation-dependent probe amplification (MLPA) to screen for BRCA1 LGRs in the index case individuals of 384 HB(O)C families who previously tested negative for BRCA1 and BRCA2 point variations, small insertions, and deletions. An alternative set of MLPA probes, long-range PCR, and real-time PCR were used to confirm positive results.

Results: We have identified 8 different BRCA1 rearrangements (del exon 1–24, del exon 8–13, del exon 11–15, del exon 14, dup exon 19–20, dup exon 20, exon 21–22 amplification, and del exon 23–24). With the exception of del exon 8–13, they are novel alterations. Overall, BRCA1 LGRs explain 1.4% of the Spanish HB(O)C families, and they account for 8.2% of all BRCA1 pathogenic variations identified in our study population. BRCA1 genetic variants affecting hybridization of commercially available MLPA probes are very rare in our population.

Conclusions: Screening for BRCA1 LGRs should be mandatory in Spanish HB(O)C families. A high proportion of country-specific rearrangements are scattered along the gene. MLPA is a robust method to screen for LGRs in our population. MLPA analysis of positive samples with an alternative set of probes, together with long-range PCR and real-time PCR, is a feasible approach to confirm results in cases in which LGR breakpoints have not been characterized.

The following articles in journals at HighWire Press have cited this article:

				M. D. Palma, S. M. Domchek, J. Stopfer, J. Erlichman, J. D. Siegfried, J. Tigges-Cardwell, B. A. Mason, T. R. Rebbeck, and K. L. Nathanson The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families Cancer Res., September 1, 2008; 68(17): 7006 - 7014. [Abstract] [Full Text] [PDF]

				R. L. Milne, A. Osorio, T. R. y Cajal, A. Vega, G. Llort, M. de la Hoya, O. Diez, M. C. Alonso, C. Lazaro, I. Blanco, et al. The Average Cumulative Risks of Breast and Ovarian Cancer for Carriers of Mutations in BRCA1 and BRCA2 Attending Genetic Counseling Units in Spain Clin. Cancer Res., May 1, 2008; 14(9): 2861 - 2869. [Abstract] [Full Text] [PDF]

				D. Huo and O. I. Olopade Genetic Testing in Diverse Populations: Are Researchers Doing Enough to Get Out the Correct Message? JAMA, December 26, 2007; 298(24): 2910 - 2911. [Full Text] [PDF]

				J. N. Weitzel, V. I. Lagos, J. S. Herzog, T. Judkins, B. Hendrickson, J. S. Ho, C. N. Ricker, K. J. Lowstuter, K. R. Blazer, G. Tomlinson, et al. Evidence for Common Ancestral Origin of a Recurring BRCA1 Genomic Rearrangement Identified in High-Risk Hispanic Families Cancer Epidemiol. Biomarkers Prev., August 1, 2007; 16(8): 1615 - 1620. [Abstract] [Full Text] [PDF]