Sequence analysis of mutations and translocations across breast cancer subtypes
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. Nature
(Impact Factor: 41.46).
06/2012; 486(7403):405-9. DOI: 10.1038/nature11154
Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.
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Available from: Ferenc A Scheeren
- "Dampening of APC inhibition of β-catenin appears to be more often due to promoter methylation (36–54%) and loss of heterozygosity (LOH) (23%) than to somatically acquired APC mutations (∼2%) in human breast cancers (Sarrio et al., 2003; Jin et al., 2001; Banerji et al., 2012; The cancer genome atlas network 2012), but the presence of the APC promoter methylation and LOH are independent of tumor size or stage (Jin et al., 2001; Sarrio et al., 2003). The APC mutations in breast cancers are typically found at sites distinct from the APC mutation cluster region in colorectal cancers and are much more frequently seen in advanced than early stage breast cancers (Furuuchi et al., 2000). "
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ABSTRACT: MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression. DOI: http://dx.doi.org/10.7554/eLife.01977.001
Available from: Dimitrios Zardavas
- "pdf/breast.pdf). Despite this ever-growing recognition of the clinical significance of the molecular characterisation of metastatic lesions in breast cancer (Shah et al, 2009; Ding et al, 2010; Navin et al, 2011), most of the molecular profiling studies reported so far have assessed primary breast cancer tumours, thus failing to inform us about the molecular evolution and the landscape of molecular changes underpinning metastatic disease (Banerji et al, 2012; Curtis et al, 2012; Ellis et al, 2012; Koboldt et al, 2012; Shah et al, 2012; Stephens et al, 2012). However, cancer cells are able to molecularly evolve, adapting to selective pressures posed by treatment, as has been shown both in the preclinical and clinical setting (Duncan et al, 2012; Balko et al, 2014). "
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ABSTRACT: Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as 'exceptional responders' or as 'rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients.
Available from: Axel Hillmer
- "Genetic changes through somatic mutations span from single nucleotide alterations to breakpoints interrupting gene contiguity, segmental copy number changes, and imbalances of entire chromosomes. The spectrum of point mutations and small insertions/deletions in breast cancers has been extensively studied and revealed a limited number of genes that are frequently mutated, such as TP53, PIK3CA, KRAS, and a larger number of rare mutations with many of unclear importance (Banerji et al. 2012; The Cancer Genome Atlas Network 2012; Shah et al. 2012; Stephens et al. 2012). The frequency of copy number gain and loss and their relationship with patient prognosis have also been examined in breast cancer (Chin et al. 2006; Hicks et al. 2006; Beroukhim et al. 2010; J€ onsson et al. 2010; Russnes et al. 2010; Staaf et al. 2010; Curtis et al. 2012). "
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ABSTRACT: Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-insert genomic DNA with matched transcriptome profiling. We found that tandem duplications appear to be early events in tumor evolution, especially in the genesis of amplicons. In a detailed reconstruction of events on chromosome 17, we found large unpaired inversions and deletions connect a tandemly duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. This series of events appeared to be unusually common when examined in larger genomic data sets of breast cancers albeit using approaches with lesser resolution. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently coamplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2-transfected human normal mammary epithelial cells. Coamplification of other functionally tested oncogenic elements in other breast tumors examined, such as RIPK2 and MYC on chromosome 8, also parallel these findings. Our analyses suggest that structural variations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously and that such oncogenic cassettes are favored during the evolution of a cancer.
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