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Screening for a BRCA2 Rearrangement in High-Risk Breast/Ovarian Cancer Families: Evidence for a Founder Effect and Analysis of the Associated Phenotypes

Patrícia M. Machado, Rita D. Brandão, Branca M. Cavaco, Joana Eugénio, Sandra Bento, Mónica Nave, Paula Rodrigues, Aires Fernandes, Fátima Vaz

From the Molecular Biology Department and Breast Cancer Risk Evaluation Clinic, Instituto Português de Oncologia de Lisboa, Francisco Gentil, Lisboa, Portugal

Address reprint requests to Fátima Vaz, MD, Consulta de Risco Familiar de Cancro da Mama e Ovário, Serviço de Oncologia Médica–Instituto Português de Oncologia, de Francisco Gentil, Rua Prof Lima Basto, 1099-023 Lisboa, Portugal; e-mail: fvaz{at}ipolisboa.min-saude.pt

Purpose: BRCA2 rearrangements are rare genetic events. A large BRCA2 genomic insertion was recurrently observed in our participants, and we sought to characterize it at the molecular and phenotypic level.

Patients and Methods: We studied 210 high-risk breast/ovarian cancer families. Fifty-three probands were fully screened for BRCA1/2 mutations, and three of 53 had a large insertion in exon 3 of BRCA2. This finding was analyzed by polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), and sequencing. An additional 157 consecutive families were screened for this mutation by a three-step PCR method. Phenotype and haplotype analysis was also performed.

Results: Sixteen BRCA mutations were observed in 19 of 53 patients (36% detection rate). A recurrent Alu motif insertion in position c.156_157 was observed after sequencing of an abnormal fragment obtained after the amplification of BRCA2 exon 3. RT-PCR revealed exon 3 skipping. Screening of this rearrangement identified 14 additional families (out of 157). In total, 17 (8%) of 210 high-risk families ascertained in our clinic were positive for this mutation. Segregation of a common haplotype (from D13S260 to D13S1695) confirmed a common origin, estimated to have occurred 2,400 to 2,600 years ago. The following four cancer phenotypes were observed in the 17 positive families: female breast (n = 9), male breast (n = 4), breast/ovarian (n = 2), and heterogeneous (n = 2). Male breast cancer was more frequently observed in c.156_157insAlu–positive families compared with negative families (23% v 12%, respectively), and 33% of all male breast cancer families with an identified BRCA mutation were c.156_157insAlu positive.

Conclusion: c.156_157insAlu is a founder mutation of Portuguese origin and is the most frequent BRCA2 rearrangement described to date.

Supported by Grant No. 47320 from Serviço de Saúde e Desenvolvimento da Fundação Calouste Gulbenkian, Lisboa, and by grants (2000/2001 and 2004/2006) from Terry Fox, Núcleo Regional Sul da Liga Portuguesa Contra o Cancro, Lisboa, Portugal.

P.M.M. and R.D.B. contributed equally to this study.

Presented in part at the 53rd Annual Meeting of the American Society of Human Genetics, November 4-8, 2003, Los Angeles, CA, and at the European Human Genetics Conference, May 7-10, 2005, Prague, Czech Republic.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Related Correspondence

• Caution Should Be Used When Interpreting Alterations Affecting the Exon 3 of the BRCA2 Gene in Breast/Ovarian Cancer Families
  Orland Díez, Sara Gutiérrez-Enríquez, Teresa Ramón y Cajal, Carmen Alonso, Judith Balmaña, and Gemma Llort
  JCO 2007 25: 5035-5036 [Full Text]

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