Teugels Erik, De Brakeleer Sylvia, Goelen Guido, Lissens Willy, Sermijn Erica, De Grève Jacques
Laboratory of Molecular and Medical Oncology, AZ-VUB, Vrije Universiteit Brussel, Laarbeeklaan 101, B1090 Brussels, Belgium.
Hum Mutat. 2005 Sep;26(3):284. doi: 10.1002/humu.9366.
Linkage analysis suggests that mutations in the BRCA1 and BRCA2 genes are responsible for cancer predisposition in more than 80% of the families with high incidence of breast/ovarian cancer. However, pathogenic mutations in the BRCA1/2 genes are generally identified in much less than half of the families investigated in a diagnostic setting with the currently used PCR-based screening protocols. Here we report the identification of two different de novo Alu element insertions within the BRCA1/2 coding sequences in three out of the 50 families in which we found a cancer predisposing mutation, suggesting that this type of mutation is much more common than suggested by their occurrence in mutation databases. The Alu insertion in the BRCA2 gene resulted in the removal of the targeted exon from the corresponding mRNA molecule. Unexpectedly the Target Site Duplications generated by both Alu element insertions contained a specific 9 bp long segment, which might eventually serve as a recognition site for the transposition machinery. Finally, in contrast to the disease causing Alu insertions reported to date, the transposon identified in the BRCA1 gene does not belong to a "young" AluY but to an AluS subfamily, indicating that some of these "old" Alu elements, which are supposed to be non-functional fossil relics, are still able to retrotranspose in vivo.
连锁分析表明，在80%以上乳腺癌/卵巢癌高发家族中，BRCA1和BRCA2基因的突变是癌症易感性的原因。然而，在目前基于PCR的筛查方案的诊断环境中，在接受调查的家族中，通常只有不到一半的家族鉴定出BRCA1/2基因的致病突变。在此，我们报告在50个家族中的3个家族中发现BRCA1/2编码序列内有两种不同的从头Alu元件插入，在这些家族中我们发现了癌症易感突变，这表明这种类型的突变比突变数据库中显示的更为常见。BRCA2基因中的Alu插入导致相应mRNA分子中靶向外显子的缺失。出乎意料的是，两种Alu元件插入产生的靶位点重复都包含一个特定的9bp长片段，这最终可能作为转座机制的识别位点。最后，与迄今报道的致病Alu插入不同，在BRCA1基因中鉴定出的转座子不属于“年轻”的AluY，而是属于AluS亚家族，这表明这些被认为是无功能化石遗迹的“古老”Alu元件中的一些仍然能够在体内进行逆转座。
