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Complex landscapes of somatic rearrangement in human breast cancer genomes

Philip J Stephens et al. Nature. .

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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Figures

Figure 1
Figure 1
Somatic rearrangements observed in six of the 24 breast cancer samples screened. (a) Genome wide circos plots of somatic rearrangements. An idiogram of a normal karyotype is shown in the outer ring. A copy number plot is represented by the blue line shown inner to the chromosome idiogram. Within the inner ring each green line denotes an intrachromosomal rearrangement and each purple line an interchromosomal rearrangement. (b) The prevalence of rearrangement architectures in individual cancers: Deletion (dark blue), tandem duplication (red), inverted orientation (green), interchromosomal rearrangements (light blue), rearrangements within amplified regions (orange). (c) Extent of overlapping microhomology at rearrangement breakpoints. The number of base pairs of microhomology is plotted on the horizontal axis.
Figure 2
Figure 2
ETV6-ITPR2, an expressed, in frame fusion gene generated by a 15Mb inversion in the primary breast cancer PD3668a. (a) Across-rearrangement PCR to confirm the presence of the somatic rearrangement. (b) RT-PCR of RNA between ETV6 exon 2 and ITPR exon 35 to confirm the presence of a chimeric expressed transcript; (c) Schematic diagram of the protein domains fused in the predicted ETV6/ITPR2 fusion protein. (d) Sequence from RT-PCR product shown in (b) confirming ETV6 exon 2 fused to ITPR2 exon 35.
Figure 3
Figure 3
Extent of overlapping microhomology at different architectural classes of rearrangement junctions. The number of base pairs of microhomology is plotted on the horizontal axis.
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