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Genetic analysis of BRCA1 and BRCA2 in breast/ovarian cancer families from Aragon (Spain): two novel truncating mutations and a large genomic deletion in BRCA1

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Abstract

We screened BRCA1 and BRCA2 germline mutations in 60 high-risk breast and/or ovarian cancer patients and 20 relatives from Aragon (Spain) by DHPLC (Denaturing High Performance Liquid Chromatography) and direct sequencing of the entire coding sequence and the splicing sites of both genes. We have identified 17 different pathogenic mutations: 8 in BRCA1 and 9 in BRCA2 in 60 unrelated patients and 50% of relatives were carriers. The prevalence of pathogenic mutations in this study was 33.33%. Two truncating mutations are novel: c.5024_5025delGA in exon 16 of BRCA1 and c.2929delC in exon 11 of BRCA2 (numbered after GenBank U14680 and U43746). Multiplex Ligation Dependent Probe Amplification (MLPA) was performed for large mutational scanning of both genes and a large genomic deletion in BRCA1 was found (DelEx8-13). Furthermore, five mutations are described for the first time in Spanish population: c.1191delC, c.3478_3479delTT and c.6633_6637delCTTAA (BRCA1) and c.3972_3975delTGAG and 3908_3909delTG (BRCA2). Three mutations have been reported previously once in Spain: c.3600_3610del11 (BRCA1), c.5804_5807delTTAA (BRCA2) and c.9246C>A (BRCA2). The mutation c.5374_5377delTATG has been found before only in two unrelated families from Castilla-Leon, Spain (BRCA2). Frequent mutations described in Spanish population have also been present: c.187_188delAG, c.5242C>A and c.5385insC in BRCA1 and c.3492_3493insT and c.9254_9258delATCAT in BRCA2. c.5242C>A, 3972_3975delTGAG and c.5804_5807delTTAA were the recurrent mutations found. Fifteen different unclassified variants were identified (25% families). Although specific BRCA1 and BRCA2 mutations are recurrently reported as a result of genetic founder effects we conclude that heterogeneous ethnicity increases the variety of mutations that can be found in Spanish populations.

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Acknowledgments

We thank the Miguel Servet Foundation for its support. We are also grateful to the patients, the clinicians and all the staff especially of the Clinical Biochemistry, Oncology and Ginecology Services (Hospital Universitario Miguel Servet, Zaragoza). We also thank to the Department of Ginecology, Hospital Clínico Universitario Lozano Blesa, Zaragoza.

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Authors and Affiliations

  1. Medical Genetics Unit, Biochemistry Service, Miguel Servet Hospital, Paseo Isabel la Catolica 1-3, 50009, Zaragoza, Spain

    M. D. Miramar, M. T. Calvo, A. Rodriguez, F. Lorente, E. Barrio & A. García de Jalón

  2. Medical Oncology Service, Miguel Servet Hospital, Zaragoza, Spain

    A. Antón & A. Herrero

  3. Ginecology Service, Miguel Servet Hospital, Zaragoza, Spain

    J. Burriel

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  1. M. D. Miramar
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Correspondence to M. D. Miramar.

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Miramar, M.D., Calvo, M.T., Rodriguez, A. et al. Genetic analysis of BRCA1 and BRCA2 in breast/ovarian cancer families from Aragon (Spain): two novel truncating mutations and a large genomic deletion in BRCA1. Breast Cancer Res Treat 112, 353–358 (2008). https://doi.org/10.1007/s10549-007-9868-1

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