Functionally Recurrent Rearrangements of the MAST Kinase and Notch Gene Families in Breast Cancer

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Nature medicine (Impact Factor: 28.05). 11/2011; 17(12):1646-51. DOI: 10.1038/nm.2580
Source: PubMed

ABSTRACT Breast cancer is a heterogeneous disease that has a wide range of molecular aberrations and clinical outcomes. Here we used paired-end transcriptome sequencing to explore the landscape of gene fusions in a panel of breast cancer cell lines and tissues. We observed that individual breast cancers have a variety of expressed gene fusions. We identified two classes of recurrent gene rearrangements involving genes encoding microtubule-associated serine-threonine kinase (MAST) and members of the Notch family. Both MAST and Notch-family gene fusions have substantial phenotypic effects in breast epithelial cells. Breast cancer cell lines harboring Notch gene rearrangements are uniquely sensitive to inhibition of Notch signaling, and overexpression of MAST1 or MAST2 gene fusions has a proliferative effect both in vitro and in vivo. These findings show that recurrent gene rearrangements have key roles in subsets of carcinomas and suggest that transcriptome sequencing could identify individuals with rare, targetable gene fusions.

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Available from: Chandan Kumar-Sinha, Aug 20, 2015
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    • "The changes of expression of these classes of genes suggest a cell cycle arrest in Shp2-deficient cells. Upregulation of Skp2, amplification of Aurka, and translocation of Notch have been detected in human breast cancers (Signoretti et al, 2002; Anand et al, 2003; Robinson et al, 2011); these genes were also implicated in senescence inhibition of different cancers such as melanoma, prostate, or colon cancer (Huck et al, 2010; Lin et al, 2010; Kang et al, 2013). Interestingly, we found that Skp2, Aurka (encoding Aurora A kinase), Dll1 (encoding a Notch ligand), and the Notch target gene Hey1 were downregulated by Shp2 ablation or inhibition (Fig 2B). "
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    ABSTRACT: In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to the inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, focal adhesion kinase, and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies, which rely on senescence induction by inhibiting Shp2 or controlling its target gene products, may be useful in blocking breast cancer. © 2015 The Authors.
    The EMBO Journal 03/2015; 34(11). DOI:10.15252/embj.201489004 · 10.75 Impact Factor
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    • "NOTCH1 and NOTCH2 gene rearrangements have been recently identified in a small subset of ER-negative breast carcinoma cell lines (Robinson et al., 2011), and most likely nonrecurrent events in one prostatic carcinomas with neuroendocrine phenotype (Lapuk et al., 2012) and one colorectal carcinoma (Wu et al., 2012). Similar to our results, fusion transcripts retained exons that encode the NOTCH intracellular domain (NICD), which is responsible for inducing the transcriptional program following NOTCH activation (Robinson et al., 2011). In this study, the index cell lines showed dependence on NOTCH signaling for proliferation and survival as well as marked reduction in proliferation after treatment with gsecretase inhibitor DAPT. "
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    ABSTRACT: Glomus tumors (GT) have been classified among tumors of perivascular smooth muscle differentiation, together with myopericytoma, myofibroma/tosis, and angioleiomyoma, based on their morphologic overlap. However, no molecular studies have been carried out to date to investigate their genetic phenotype and to confirm their shared pathogenesis. RNA sequencing was performed in three index cases (GT1, malignant GT; GT2, benign GT and M1, multifocal myopericytoma), followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. A gene fusion involving MIR143 in band 5q32 was identified in both GTs with either NOTCH2 in 1p13 in GT1 or NOTCH1 in 9q34 in GT2, but none in M1. After being validated by FISH and RT-PCR, these abnormalities were screened on 33 GTs, 6 myopericytomas, 9 myofibroma/toses, 18 angioleiomyomas and in a control group of 5 sino-nasal hemangiopericytomas. Overall NOTCH2 gene rearrangements were identified in 52% of GT, including all malignant cases and one NF1-related GT. No additional cases showed NOTCH1 rearrangement. As NOTCH3 shares similar functions with NOTCH2 in regulating vascular smooth muscle development, the study group was also investigated for abnormalities in this gene by FISH. Indeed, NOTCH3 rearrangements were identified in 9% of GTs, all present in benign soft tissue GT, one case being fused to MIR143. Only 1/18 angioleiomyomas showed NOTCH2 gene rearrangement, while all the myopericytomas and myofibroma/toses were negative. In summary, we describe novel NOTCH1-3 rearrangements in benign and malignant, visceral, and soft tissue GTs. © 2013 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 11/2013; 52(11). DOI:10.1002/gcc.22102 · 3.84 Impact Factor
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    • "In breast cancer, a recurrent fusion with a low frequency, SEC16A- NOTCH1, has been reported [15]. For CRC, there are three recent reports of recurrent fusion transcripts [13] [16] [17], but all of them occur in low frequencies. "
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    ABSTRACT: Colorectal cancer (CRC) is the third most common cancer disease in the Western world, and about 40% of the patients die from this disease. The cancer cells are commonly genetically unstable, but only a few low-frequency recurrent fusion genes have so far been reported for this disease. In this study, we present a thorough search for novel fusion transcripts in CRC using high-throughput RNA sequencing. From altogether 220 million paired-end sequence reads from seven CRC cell lines, we identified 3391 candidate fused transcripts. By stringent requirements, we nominated 11 candidate fusion transcripts for further experimental validation, of which 10 were positive by reverse transcription-polymerase chain reaction and Sanger sequencing. Six were intrachromosomal fusion transcripts, and interestingly, three of these, AKAP13-PDE8A, COMMD10-AP3S1, and CTB-35F21.1-PSD2, were present in, respectively, 18, 18, and 20 of 21 analyzed cell lines and in, respectively, 18, 61, and 48 (17%-58%) of 106 primary cancer tissues. These three fusion transcripts were also detected in 2 to 4 of 14 normal colonic mucosa samples (14%-28%). Whole-genome sequencing identified a specific genomic breakpoint in COMMD10-AP3S1 and further indicates that both the COMMD10-AP3S1 and AKAP13-PDE8A fusion transcripts are due to genomic duplications in specific cell lines. In conclusion, we have identified AKAP13-PDE8A, COMMD10-AP3S1, and CTB-35F21.1-PSD2 as novel intrachromosomal fusion transcripts and the most highly recurring chimeric transcripts described for CRC to date. The functional and clinical relevance of these chimeric RNA molecules remains to be elucidated.
    Translational oncology 10/2013; 6(5):546-53. DOI:10.1593/tlo.13457 · 3.40 Impact Factor
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