Case report
A novel deletion of BRCA1 gene that eliminates the ATG initiation codon without affecting the promoter region

https://doi.org/10.1016/j.cca.2009.02.020Get rights and content

Abstract

Background

Point mutations in the highly penetrant cancer susceptibility gene BRCA1 are responsible for the majority of hereditary breast and/or ovarian cancer. We describe a novel large rearrangement of the BRCA1 gene identified in an Italian woman affected by an early onset bilateral breast cancer and a family history of hereditary breast cancer. The proband and her parents were negative for the presence of point mutations in BRCA1 and BRCA2 genes.

Methods

Multiplex ligation-dependent probe amplification (MLPA) was used to detect rearrangements in the BRCA1 gene. The breakpoint of the rearrangement identified in the proband was defined by restriction mapping and PCR amplification. BRCA1 mRNA encoded by the mutant allele was isolated from peripheral blood.

Results

The proband was heterozygous for a 9.1 kb deletion spanning from intron 1 to intron 3 (g.1238_10350del) that eliminates exons 2 and 3 in the mature mRNA. In mutant mRNA exon 1a joins directly to exon 5 with no disruption of the reading frame.

Conclusions

This deletion that eliminates the ATG initiation site in exon 2 and the sequence located in exons 2 and 3 encoding part of the RING finger domain of BRCA1 protein, is expected to abolish the function of this protein.

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.

References (23)

  • H. Eerola et al.

    Histopathological features of breast tumours in BRCA1, BRCA2 and mutation-negative breast cancer families

    Breast Cancer Res

    (2005)
    • 1

    Tel.: +39 059 2055435; fax: +39 059 2055426.

    2

    Tel.: +39 059 2055581; fax: +39 059 2055426.

    3

    Tel.: +39 059 4224334; fax: +39 059 4224152.

    4

    Tel.: +39 059 2055423; fax: +39 059 2055426.

    View full text
    Copyright © 2009 Published by Elsevier B.V.