De novo Alu element insertions targeted to a sequence common to the BRCA1 and BRCA2 genes

Abstract

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.

Epigenetic mechanisms and cancer: An interface between the environment and the genome

“…the chromosomal instability generated by the hypomethylation of repetitive sequences, abnormal transcription of repetitive elements and insertional mutagenesis may occur, both of which may increase the risk of tumor formation. [168][169][170] Loss of imprinting (LOI) may also be a consequence of global hypomethylation. 171 Genomic imprinting conditions the parental genome during gametogenesis ensuring that a specific locus is exclusively expressed from either the maternal or paternal genome in the offspring.…”

Cancer predisposing missense and protein truncatingBARD1mutations in non-BRCA1orBRCA2breast cancer families

“…However, these mutations are generally found in only 20-30% of high risk breast and/or ovarian cancer families. Limitations of currently used mutation screening methods may explain the low recovery rates [Teugels et al, 2005]. It is generally accepted that mutations in other genes like CHEK2, ATM, PALB2 and BRIP1 could be the cancer predisposing factor in some breast cancer families [Meijers-Heijboer et al, 2002;Erkko et al, 2006;Rahman et al, 2006;Renwick et al, 2006;Seal et al, 2006], but the observed lower penetrance of these mutations and a less obvious cosegregation pattern with the disease suggest that these mutations act according to a polygenic model [Antoniou et al, 2001Ponder, 2001;Pharoah et al, 2002].…”

The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology

“…Ten out of 11 (90.1%) of these insertions disrupted coding exons, while the remaining insertion caused exon "skipping" (Ganguly et al 2003). Similar germline MEIs have been implicated in a range of other human diseases, including neurofibromatosis (Wallace et al 1991), Duchenne muscular dystrophy (Narita et al 1993), cystic fibrosis (Chen et al 2008), retinitis pigmentosis (Schwahn et al 1998), beta-thalassemia (Divoky et al 1996;Kimberland et al 1999;Lanikova et al 2013), various cancers (Miki et al 1996;Teugels et al 2005), and other diseases (e.g., Janicic et al 1995;Claverie-Martin et al 2003;Watanabe et al 2005). As above, most of these diseases were caused by MEIs that disrupted the coding exons of genes or caused exon skipping, although disease-causing MEIs also have been identified in the promoters (Lanikova et al 2013) and untranslated regions (UTRs) of protein-coding genes (Watanabe et al 2005).…”