Bonatti Fabrizia, Pepe Chiara, Tancredi Mariella, Lombardi Grazia, Aretini Paolo, Sensi Elisa, Falaschi Elisabetta, Cipollini Giovanna, Bevilacqua Generoso, Caligo Maria Adelaide
Section of Genetic Oncology, Division of Surgical, Molecular and Ultrastructural Pathology, University of Pisa and Pisa University Hospital, Via Roma, Pisa, Italy.
Cancer Genet Cytogenet. 2006 Oct 15;170(2):93-101. doi: 10.1016/j.cancergencyto.2006.05.005.
Alterations in BRCA1 and BRCA2 genes account for a large proportion of hereditary breast and ovarian cancers. Mutations and variants of unknown pathological significance have been identified in both genes; however, most of them have been studied only at the genomic level, and their effect on mRNA expression remains unknown. We identified two BRCA1 and six BRCA2 splice site variants, and one BRCA2 alteration at exon 14. Our aim was to ascertain the effect on RNA processing of the variants still unclassified. We found that 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 lead to aberrant transcripts in lymphocytes. Five of these six splice site variants caused a complete inactivation of the mutant allele because they produced frameshift similar to previously described deleterious exonic variants. Therefore, we consider them to be true deleterious mutations, possibly associated with an increased lifetime risk of breast or ovarian cancer. BRCA1 c.IVS17 + 6C>G, BRCA2 c.IVS12-9del4, and BRCA2 IVS1-9del3 represent rare variants, not disrupting normal mRNA processing. The last two BRCA2 genetic variants had not been reported in the Breast Cancer Information Core BIC database.
BRCA1和BRCA2基因的改变在遗传性乳腺癌和卵巢癌中占很大比例。在这两个基因中均已鉴定出具有未知病理意义的突变和变异；然而，其中大多数仅在基因组水平上进行了研究，它们对mRNA表达的影响仍然未知。我们鉴定出两个BRCA1剪接位点变异和六个BRCA2剪接位点变异，以及一个位于第14外显子的BRCA2改变。我们的目的是确定仍未分类的变异对RNA加工的影响。我们发现，BRCA1 c.IVS11 + 1G>A、BRCA2 c.7252_7272delinsTG、BRCA2 c.IVS2 + 1G>A、BRCA2 c.IVS13-2A>G、BRCA2 c.IVS21 + 4A>G和BRCA2 c.9345G>A会导致淋巴细胞中出现异常转录本。这六个剪接位点变异中的五个导致突变等位基因完全失活，因为它们产生的移码类似于先前描述的有害外显子变异。因此，我们认为它们是真正的有害突变，可能与乳腺癌或卵巢癌终生风险增加有关。BRCA1 c.IVS17 + 6C>G、BRCA2 c.IVS12-9del4和BRCA2 IVS1-9del3代表罕见变异，不会破坏正常的mRNA加工。最后两个BRCA2基因变异在乳腺癌信息核心BIC数据库中尚未见报道。
