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Stephens, P. J. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005-1010

Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Nature (Impact Factor: 42.35). 12/2009; 462(7276):1005-10. DOI: 10.1038/nature08645
Source: PubMed

ABSTRACT Multiple somatic rearrangements are often found in cancer genomes; however, the underlying processes of rearrangement and their contribution to cancer development are poorly characterized. Here we use a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by non-homologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. The study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development.

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Available from: Anieta M Sieuwerts, Sep 03, 2015
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    • "First, and paradoxically, rearrangements are expected to occur in gene-dense, actively transcribed regions of the genome. A recent survey of rearrangements in human cancers shows that this is indeed the case (Stephens et al., 2009). Additionally, this same study showed that the large majority of breakpoints in cancer occur with a distance of 2 Mb, much closer than expected by chance but consistent with the strong influence from the intra-nucleus chromatin interactions that our model accounts for. "
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    • "For genetic risk, mutations in tumor suppressor genes BRCA 1 and 2 are the major predisposing factors for BC but these mutations are rare. On the other hand, 20–30% of BC may have familial basis (Lynch et al., 2008; Stephens et al., 2009). In fact, BRCA mutations affect DNA repair activities (Roy et al., 2012) but mutations in genes that affect other DNA repair pathways may also be involved (Berwick and Vineis, 2000; Stephens et al., 2012; Nik-Zainal et al., 2012). "
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    • "As still most NGS technologies sequence shorter segments (hundreds of bases), detection of rearrangements close to centromeres are easily missed due to repetitive sequences that cannot be accurately mapped. This is illustrated by two of the MicMa samples in this study which previously were analyzed by pairedend sequencing (Stephens et al., 2009) and the results illustrated in genome-wide circos plots, displaying somatic rearrangements like insertion, deletions and translocations, but no translocation between chromosomes 1 and 16 was identified (Figure 6). However, QM-FISH performed on imprints from the same samples detected the translocation between chromosome 1 and 16 in multiple cells from both samples (Fig. 6). "
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