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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We are grateful to M. Lambros, F. Geyer and R. Vatcheva for their assistance in the FISH experiments. We would like to acknowledge the support of the Kay Kendall Leukaemia Fund under Grant KKL282, Human Frontiers Award reference LT000561/2009-L, the Dana-Farber/Harvard SPORE in breast cancer under NCI grant reference CA089393, Breakthrough Breast Cancer, the Research Council of Norway Grants no. 155218 and 175240, and the Wellcome Trust under grant reference 077012/Z/05/Z.
Author Contributions M.R.S., P.A.F., P.J.C. and P.J.S. designed the experiment. S.E., D.J.M., P.J.S., M-L.L., I.V., L.J.M., J.B., M.A.Q., H.S., C.C., R.N., A.M.S., A.L., J.W.M.M. and C.Latimer carried out laboratory analyses. J.A.F., J.S.R.-F., L.v.V., A.L.R. D.P.S. and A.-L.B.-D. provided clinical samples. P.J.S., D.J.M., I.V., M.-L.L., E.D.P., J.T.S., L.A.S., C.Leroy, C.D.G., M.J., J.W.T., K.W.L., P.J.C., P.A.F., J.S.R.-F., J.W.M.M., A.M.S., J.A.F., M.R.S., H.E.G.R., A.L.R., A.-L.B.-D., L.v.V., A.L., P.J.C. and P.A.F. performed data analysis, informatics and statistics. M.R.S. wrote the manuscript with comments from P.J.S., P.A.F., P.J.C., A.-L.B.-D., J.S.R.-F., J.A.F., A.L.R., D.P.S. and L.v.V.
Summary of somatic rearrangements found in 24 breast cancers
Variation in the prevalence of rearrangement architectures in individual breast cancer genomes.
Base pair resolution of rearrangement breakpoints.
GC content analysis at rearrangement breakpoints.
Evaluation of motif enrichment at rearrangement breakpoints.
Internally rearranged genes.
Known cancer genes that are rearranged.