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: 41.46). 12/2009; 462(7276):1005-10. DOI: 10.1038/nature08645
Source: PubMed


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
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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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    ABSTRACT: Genomic rearrangements are a major source of evolutionary divergence in eukaryotic genomes, a cause of genetic diseases and a hallmark of tumor cell progression, yet the mechanisms underlying their occurrence and evolutionary fixation are poorly understood. Statistical associations between breakpoints and specific genomic features suggest that genomes may contain elusive "fragile regions" with a higher propensity for breakage. Here, we use ancestral genome reconstructions to demonstrate a near-perfect correlation between gene density and evolutionary rearrangement breakpoints. Simulations based on functional features in the human genome show that this pattern is best explained as the outcome of DNA breaks that occur in open chromatin regions coming into 3D contact in the nucleus. Our model explains how rearrangements reorganize the order of genes in an evolutionary neutral fashion and provides a basis for understanding the susceptibility of "fragile regions" to breakage. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Cell Reports
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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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    ABSTRACT: Purpose: The incidence of breast cancer (BC) in China has been rapidly increasing. We hypothesize that China-specific risk factors, both life-style and inherent ones, contribute to the problem. Method: We have conducted an epidemiology and functional DNA repair investigation to identify risk factors for the development of BC in Shantou, China. Results: Our survey of 372 patients and 419 matched normal controls confirmed the significant risk from many universal factors: high BMI, low education level, low fruit intake and sedate lifestyle. Significant risk factors can be organized into endogenous ones (low education and cooking with lard instead of vegetable oil) and externally-introduced ones (sedate life-style and cigarette smoking). We also found highly significant risk from passive exposure to cigarette smoke. Using the Challenge-Comet assay and blood samples from 57 patients who did not inherit the tumor suppressor BRCA gene mutations and 62 matched normal controls; we showed that reduced functional DNA repair capacity was a significant risk factor. In addition, the reduced repair capacity was associated with lymph node metastasis, and with tumors that had negative ER receptor and over-expression of Her-2. Conclusion: Our study indicates that combined externally-introduced and endogenous life-style factors were involved with the increased incidence of BC in China. We also showed, for the first time, that inherent deficiency in DNA repair function was a significant risk factor for BC. The inherent deficiency can interact with other risk factors to significantly increase risk for BC. In addition, the reduced repair capacity was associated with certain clinical features that are indicative of poor prognosis. In this context, it is possible to integrate DNA repair capacity knowledge in promoting prevention of BC and in enhancing personalized therapeutic protocols.
    Full-text · Article · Jan 2015 · International Journal of Hygiene and Environmental Health
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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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    ABSTRACT: In situ detection of genomic alterations in cancer provides information at the single cell level, making it possible to investigate genomic changes in cells in a tissue context. Such topological information is important when studying intratumor heterogeneity as well as alterations related to different steps in tumor progression. We developed a quantitative multigene fluorescence in situ hybridization (QM FISH) method to detect multiple genomic regions in single cells in complex tissues. As a “proof of principle” we applied the method to breast cancer samples to identify partners in whole arm (WA) translocations. WA gain of chromosome arm 1q and loss of chromosome arm 16q are among the most frequent genomic events in breast cancer. By designing five specific FISH probes based on breakpoint information from comparative genomic hybridization array (aCGH) profiles, we visualized chromosomal translocations in clinical samples at the single cell level. By analyzing aCGH data from 295 patients with breast carcinoma with known molecular subtype, we found concurrent WA gain of 1q and loss of 16q to be more frequent in luminal A tumors compared to other molecular subtypes. QM FISH applied to a subset of samples (n = 26) identified a derivative chromosome der(1;16)(q10;p10), a result of a centromere-close translocation between chromosome arms 1q and 16p. In addition, we observed that the distribution of cells with the translocation varied from sample to sample, some had a homogenous cell population while others displayed intratumor heterogeneity with cell-to-cell variation. Finally, for one tumor with both preinvasive and invasive components, the fraction of cells with translocation was lower and more heterogeneous in the preinvasive tumor cells compared to the cells in the invasive component. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Dec 2014 · Genes Chromosomes and Cancer
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