Case reportA novel deletion of BRCA1 gene that eliminates the ATG initiation codon without affecting the promoter region
Introduction
Systematic analysis of BRCA1 gene in hereditary breast cancer (HBC) families has resulted in the identification of over 1000 different disease-causing germline mutations [1].
BRCA1 gene mutations account for 52% of HBC families but the percentage of germline mutations detected in this gene is lower than expected according to the estimates of genetic linkage data [2], [3], [4]. This relatively low number of germline mutations can partly be explained by the BRCA1 gene alterations that escape the most common methods for the detection of point/minute mutations [2], [5]. MLPA is a technique that allows the discovery of large genomic rearrangements (LGRs) that can alter the gene function causing the synthesis of an aberrant protein [6]. Many different LGRs in BRCA1 gene have been reported. Most of them are deletions, but duplications, amplifications or combined deletion/insertion events have also been described [7]. During a survey of breast cancer patients, selected for the analysis of BRCA1 and BRCA2 genes [8], we found a patient heterozygous for a novel rearrangement of BRCA1 gene and we characterized it. This novel mutation leads to the elimination of the ATG initiation codon without affecting the promoting area of the gene.
Section snippets
Family
The proband was a 38 year-old female with an early onset bilateral breast cancer diagnosed at 31 and 37 years of age respectively. The histological features (infiltrating ductal carcinoma, grading III, estrogen and progesterone receptors negative, Ki67 equal to 57%, c-ErbB2 negative) were similar in both cancers.
The proband's family (Fig. 1), originating from Northern Italy, included 53 individuals with a high incidence of female breast cancers (7 positive cases out of 27 women in both maternal
Results
The sequence of BRCA1 gene in the proband did not reveal point/minute mutations. The proband was found to be heterozygous for c.8415 G>T transversion in exon 18 of BRCA2 gene (K2729N), a non synonymous amino acid substitution that has not been associated with a specific biological effect [1] [GenBank: NM_000059.3, NP_000050]. This variant was also found in proband's mother. To ascertain whether the proband was a carrier of a large rearrangement of BRCA1 gene we used MLPA technique. The changes
Discussion
Previously, Mazoyer [17], using a different technique like southern blot, reported many rearrangements in BRCA1 gene, including the deletion of exons 1–2 and the single deletion of exon 3. In this study we report a novel partial deletion of BRCA1 gene spanning from the 3′ end of intron 1b to the 5′ end of intron 3 found in a 38 year-old woman with early onset bilateral breast cancer. The detailed characterization of breakpoint suggested that this deletion was probably the result of an unequal
Acknowledgements
We thank the patients, their relatives and normal subjects for their participation.
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Cited by (8)
Detection of BRCA1/2 large genomic rearrangements in breast and ovarian cancer patients: an overview of the current methods
2019, Expert Review of Molecular DiagnosticsAssessment of the functional impact of germline BRCA1/2 variants located in non-coding regions in families with breast and/or ovarian cancer predisposition
2018, Breast Cancer Research and TreatmentThe importance of BRCA1 and BRCA2 genes mutations in breast cancer development
2016, Medical Journal of the Islamic Republic of Iran
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