title: Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer.
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.
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Robinson
authors.forename: Shanker
authors.initials: S
authors.lastname: Kalyana-Sundaram
authors.forename: Yi-Mi
authors.initials: YM
authors.lastname: Wu
authors.forename: Sunita
authors.initials: S
authors.lastname: Shankar
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Bushra
authors.initials: B
authors.lastname: Ateeq
authors.forename: Irfan A
authors.initials: IA
authors.lastname: Asangani
authors.forename: Matthew
authors.initials: M
authors.lastname: Iyer
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Grasso
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lonigro
authors.forename: Michael
authors.initials: M
authors.lastname: Quist
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Jing
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sabel
authors.forename: Celina G
authors.initials: CG
authors.lastname: Kleer
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Maryou B
authors.initials: MB
authors.lastname: Lambros
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Chandan
authors.initials: C
authors.lastname: Kumar-Sinha
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000483:Alleles; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D015321:Gene Rearrangement; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules; D005810:Multigene Family; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D008869:Microtubule-Associated Proteins; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D051880:Receptors, Notch; D017346:Protein Serine-Threonine Kinases
references.citation: Leukemia. 2006 Jul;20(7):1279-87
references.pmid: 16688224
references.citation: Annu Rev Genet. 1998;32:495-519
references.pmid: 9928489
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5012-7
references.pmid: 20194747
references.citation: Nature. 2010 Apr 15;464(7291):999-1005
references.pmid: 20393555
references.citation: Nature. 1992 Sep 10;359(6391):162-5
references.pmid: 1522903
references.citation: J Natl Cancer Inst. 1960 Jul;25:85-109
references.pmid: 14427847
references.citation: Nature. 2009 Mar 5;458(7234):97-101
references.pmid: 19136943
references.citation: Oncogene. 2010 Aug 12;29(32):4543-54
references.pmid: 20562911
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9262-7
references.pmid: 16751266
references.citation: Brain Res. 2008 Feb 21;1195:12-9
references.pmid: 18206861
references.citation: J Neurochem. 2001 Jan;76(1):173-81
references.pmid: 11145990
references.citation: Science. 2005 Oct 28;310(5748):644-8
references.pmid: 16254181
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12353-8
references.pmid: 19592507
references.citation: Nature. 2009 Dec 24;462(7276):1005-10
references.pmid: 20033038
references.citation: Cancer Cell. 2002 Nov;2(5):367-76
references.pmid: 12450792
references.citation: Nat Rev Cancer. 2008 Jul;8(7):497-511
references.pmid: 18563191
references.citation: Curr Opin Genet Dev. 2009 Feb;19(1):82-91
references.pmid: 19233641
references.citation: Nature. 2009 Oct 8;461(7265):809-13
references.pmid: 19812674