Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families

Marco Montagna, Maurizia Dalla Palma, Chiara Menin, Simona Agata, Arcangela De Nicolo, Luigi Chieco-Bianchi, Emma D. D'Andrea

Research output: Contribution to journalArticle

Abstract

The recent identification of major genomic rearrangements in breast and breast/ovarian cancer families has widened the mutational spectrum of the BRCA1 gene, thus increasing the number of informative patients who can benefit from molecular screening. Numerous types of alterations have been identified in different populations with variable frequencies, probably due to both ethnic diversity and the technical approach employed. In fact, although several methods have been successfully used to detect large genomic deletions and insertions, most are laborious, time-consuming, and of variable sensitivity. In order to estimate the contribution of BRCA1 genomic rearrangements to breast/ovarian cancer predisposition in Italian families, we applied, for the first time as a diagnostic tool, the recently described multiplex ligation-dependent probe amplification (MLPA) methodology. Among the 37 hereditary breast/ovarian cancer (HBOC) families selected, all had a high prior probability of BRCA1 mutation, and 15 were previously shown to carry a mutation in either the BRCA2 (five families) or BRCA1 gene (10 families, including one genomic rearrangement). The application of BRCA1-MLPA to the remaining 22 uninformative families allowed the identification of five additional genomic rearrangements. Moreover, we observed that loss of constitutive heterozygosity of polymorphic markers in linkage disequilibrium is predictive of such BRCA1 alterations. By means of this approach, we demonstrate that BRCA1 genomic deletions account for more than one-third (6/15) of the pathogenic BRCA1 mutations in our series. We therefore propose to systematically include MLPA in the BRCA1 mutational analysis of breast/ovarian cancer families.

Original languageEnglish
Pages (from-to)1055-1061
Number of pages7
JournalHuman Molecular Genetics
Volume12
Issue number9
DOIs
Publication statusPublished - May 1 2003

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Ovarian Neoplasms
Breast Neoplasms
Mutation
Multiplex Polymerase Chain Reaction
BRCA1 Gene
Loss of Heterozygosity
Linkage Disequilibrium
Breast
Population

ASJC Scopus subject areas

  • Genetics

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Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. / Montagna, Marco; Palma, Maurizia Dalla; Menin, Chiara; Agata, Simona; De Nicolo, Arcangela; Chieco-Bianchi, Luigi; D'Andrea, Emma D.

In: Human Molecular Genetics, Vol. 12, No. 9, 01.05.2003, p. 1055-1061.

Research output: Contribution to journalArticle

Montagna, Marco ; Palma, Maurizia Dalla ; Menin, Chiara ; Agata, Simona ; De Nicolo, Arcangela ; Chieco-Bianchi, Luigi ; D'Andrea, Emma D. / Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. In: Human Molecular Genetics. 2003 ; Vol. 12, No. 9. pp. 1055-1061.
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