RNA-based analysis of BRCA1 and BRCA2 gene alterations
Fabrizia Bonatti1, Chiara Pepe, Mariella Tancredi
1Section of Genetic Oncology, Division of Surgical, Molecular and Ultrastructural Pathology, University of Pisa and Pisa University Hospital, Via Roma, Pisa, Italy.
Cancer Genetics and Cytogenetics
|October 3, 2006
Summary
New research reveals that several BRCA1 and BRCA2 gene variants disrupt mRNA processing, potentially causing hereditary breast and ovarian cancers. Some variants lead to complete gene inactivation, indicating they are true deleterious mutations.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- BRCA1 and BRCA2 gene alterations are significant causes of hereditary breast and ovarian cancers.
- Many mutations and variants of unknown significance exist, with their impact on mRNA expression largely unstudied.
- Understanding RNA processing effects is crucial for accurate variant classification.
Purpose of the Study:
- To investigate the effect of unclassified BRCA1 and BRCA2 variants on RNA processing.
- To determine if identified variants lead to aberrant mRNA transcripts.
- To classify variants as deleterious or benign based on their impact on gene function.
Main Methods:
- Identification of BRCA1 and BRCA2 splice site variants and an exon 14 alteration.
- Analysis of RNA processing in lymphocytes for selected variants.
- Assessment of transcript integrity and potential frameshift mutations.
Main Results:
- Six specific variants (BRCA1 c.IVS11 + 1G>A, BRCA2 c.7252_7272delinsTG, BRCA2 c.IVS2 + 1G>A, BRCA2 c.IVS13-2A>G, BRCA2 c.IVS21 + 4A>G, and BRCA2 c.9345G>A) resulted in aberrant transcripts.
- Five of these variants caused complete allele inactivation due to frameshifts, classifying them as deleterious.
- Three variants (BRCA1 c.IVS17 + 6C>G, BRCA2 c.IVS12-9del4, BRCA2 IVS1-9del3) did not disrupt normal mRNA processing and are considered rare.
Conclusions:
- Several BRCA1 and BRCA2 splice site variants significantly impact mRNA processing, leading to gene inactivation.
- These deleterious variants are likely associated with an increased lifetime risk of breast and ovarian cancer.
- Rare variants not affecting mRNA processing were also identified, with some novel to the BIC database.
