Breakpoint Analysis of Transcriptional and Genomic Profiles Uncovers Novel Gene Fusions Spanning Multiple Human Cancer Types

English version České info

Gene fusions, like BCR/ABL1 in chronic myelogenous leukemia, have long been recognized in hematologic and mesenchymal malignancies. The recent finding of gene fusions in prostate and lung cancers has motivated the search for pathogenic gene fusions in other malignancies. Here, we developed a “breakpoint analysis” pipeline to discover candidate gene fusions by tell-tale transcript level or genomic DNA copy number transitions occurring within genes. Mining data from 974 diverse cancer samples, we identified 198 candidate fusions involving annotated cancer genes. From these, we validated and further characterized novel gene fusions involving ROS1 tyrosine kinase in angiosarcoma (CEP85L/ROS1), SLC1A2 glutamate transporter in colon cancer (APIP/SLC1A2), RAF1 kinase in pancreatic cancer (ATG7/RAF1) and anaplastic astrocytoma (BCL6/RAF1), EWSR1 in melanoma (EWSR1/CREM), CDK6 kinase in T-cell acute lymphoblastic leukemia (FAM133B/CDK6), and CLTC in breast cancer (CLTC/VMP1). Notably, while these fusions involved known cancer genes, all occurred with novel fusion partners and in previously unreported cancer types. Moreover, several constituted druggable targets (including kinases), with therapeutic implications for their respective malignancies. Lastly, breakpoint analysis identified new cell line models for known rearrangements, including EGFRvIII and FIP1L1/PDGFRA. Taken together, we provide a robust approach for gene fusion discovery, and our results highlight a more widespread role of fusion genes in cancer pathogenesis.

Vyšlo v časopise: Breakpoint Analysis of Transcriptional and Genomic Profiles Uncovers Novel Gene Fusions Spanning Multiple Human Cancer Types. PLoS Genet 9(4): e32767. doi:10.1371/journal.pgen.1003464
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003464

Souhrn

Zdroje

1. AmanP (1999) Fusion genes in solid tumors. Semin Cancer Biol 9: 303–318.

2. MitelmanF, JohanssonB, MertensF (2004) Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nat Genet 36: 331–334.

3. MitelmanF, JohanssonB, MertensF (2007) The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7: 233–245.

4. TomlinsSA, RhodesDR, PernerS, DhanasekaranSM, MehraR, et al. (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310: 644–648.

5. SodaM, ChoiYL, EnomotoM, TakadaS, YamashitaY, et al. (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448: 561–566.

6. TomlinsSA, LaxmanB, DhanasekaranSM, HelgesonBE, CaoX, et al. (2007) Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448: 595–599.

7. KwakEL, BangYJ, CamidgeDR, ShawAT, SolomonB, et al. (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363: 1693–1703.

8. TallmanMS (2002) Advancing the treatment of hematologic malignancies through the development of targeted interventions. Semin Hematol 39: 1–5.

9. RowleyJD (1973) Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243: 290–293.

10. de KleinA, van KesselAG, GrosveldG, BartramCR, HagemeijerA, et al. (1982) A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 300: 765–767.

11. de TheH, LavauC, MarchioA, ChomienneC, DegosL, et al. (1991) The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66: 675–684.

12. KakizukaA, MillerWHJr, UmesonoK, WarrellRPJr, FrankelSR, et al. (1991) Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell 66: 663–674.

13. EguchiM, Eguchi-IshimaeM, TojoA, MorishitaK, SuzukiK, et al. (1999) Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25). Blood 93: 1355–1363.

14. KnezevichSR, McFaddenDE, TaoW, LimJF, SorensenPH (1998) A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 18: 184–187.

15. TognonC, KnezevichSR, HuntsmanD, RoskelleyCD, MelnykN, et al. (2002) Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2: 367–376.

16. ForghieriF, MorselliM, PotenzaL, MaccaferriM, PedrazziL, et al. (2011) Chronic eosinophilic leukaemia with ETV6-NTRK3 fusion transcript in an elderly patient affected with pancreatic carcinoma. Eur J Haematol 86: 352–355.

17. PalanisamyN, AteeqB, Kalyana-SundaramS, PfluegerD, RamnarayananK, et al. (2010) Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 16: 793–798.

18. JonesDT, KocialkowskiS, LiuL, PearsonDM, BacklundLM, et al. (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68: 8673–8677.

19. BassAJ, LawrenceMS, BraceLE, RamosAH, DrierY, et al. (2011) Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet 43: 964–968.

20. BergerMF, LevinJZ, VijayendranK, SivachenkoA, AdiconisX, et al. (2010) Integrative analysis of the melanoma transcriptome. Genome Res 20: 413–427.

21. CampbellPJ, StephensPJ, PleasanceED, O'MearaS, LiH, et al. (2008) Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 40: 722–729.

22. JuYS, LeeWC, ShinJY, LeeS, BleazardT, et al. (2011) Fusion of KIF5B and RET transforming gene in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res

23. MaherCA, Kumar-SinhaC, CaoX, Kalyana-SundaramS, HanB, et al. (2009) Transcriptome sequencing to detect gene fusions in cancer. Nature 458: 97–101.

24. MaherCA, PalanisamyN, BrennerJC, CaoX, Kalyana-SundaramS, et al. (2009) Chimeric transcript discovery by paired-end transcriptome sequencing. Proc Natl Acad Sci U S A 106: 12353–12358.

25. PfluegerD, TerryS, SbonerA, HabeggerL, EsguevaR, et al. (2011) Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing. Genome Res 21: 56–67.

26. StephensPJ, McBrideDJ, LinML, VarelaI, PleasanceED, et al. (2009) Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462: 1005–1010.

27. TaoJ, DengNT, RamnarayananK, HuangB, OhHK, et al. (2011) CD44-SLC1A2 gene fusions in gastric cancer. Sci Transl Med 3: 77ra30.

28. KawamataN, OgawaS, ZimmermannM, NiebuhrB, StockingC, et al. (2008) Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray. Proc Natl Acad Sci U S A 105: 11921–11926.

29. McLendonR, FriedmanA, BignerD, Van MeirE, BratD, et al. (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455: 1061–1068.

30. BellD, BerchuckA, BirrerM, ChienJ, CramerD, et al. (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474: 609–615.

31. BignellGR, GreenmanCD, DaviesH, ButlerAP, EdkinsS, et al. (2010) Signatures of mutation and selection in the cancer genome. Nature 463: 893–898.

32. O'NeilJ, TchindaJ, GutierrezA, MoreauL, MaserRS, et al. (2007) Alu elements mediate MYB gene tandem duplication in human T-ALL. J Exp Med 204: 3059–3066.

33. ReinholdWC, MergnyJL, LiuH, RyanM, PfisterTD, et al. (2010) Exon array analyses across the NCI-60 reveal potential regulation of TOP1 by transcription pausing at guanosine quartets in the first intron. Cancer Res 70: 2191–2203.

34. ShainAH, GiacominiCP, MatsukumaK, KarikariCA, BashyamMD, et al. (2012) Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer. Proc Natl Acad Sci U S A 109: E252–259.

35. LovfM, ThomassenGO, BakkenAC, CelestinoR, FioretosT, et al. (2011) Fusion gene microarray reveals cancer type-specificity among fusion genes. Genes Chromosomes Cancer 50: 348–357.

36. LinE, LiL, GuanY, SorianoR, RiversCS, et al. (2009) Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. Mol Cancer Res 7: 1466–1476.

37. JhavarS, ReidA, ClarkJ, Kote-JaraiZ, ChristmasT, et al. (2008) Detection of TMPRSS2-ERG translocations in human prostate cancer by expression profiling using GeneChip Human Exon 1.0 ST arrays. J Mol Diagn 10: 50–57.

38. WangL, MotoiT, KhaninR, OlshenA, MertensF, et al. (2012) Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Genes Chromosomes Cancer 51: 127–139.

39. LiF, FengY, FangR, FangZ, XiaJ, et al. (2012) Identification of RET gene fusion by exon array analyses in “pan-negative” lung cancer from never smokers. Cell Res 22: 928–931.

40. FutrealPA, CoinL, MarshallM, DownT, HubbardT, et al. (2004) A census of human cancer genes. Nat Rev Cancer 4: 177–183.

41. RitzA, ParisPL, IttmannMM, CollinsC, RaphaelBJ (2011) Detection of recurrent rearrangement breakpoints from copy number data. BMC Bioinformatics 12: 114.

42. TibshiraniR, WangP (2008) Spatial smoothing and hot spot detection for CGH data using the fused lasso. Biostatistics 9: 18–29.

43. AcquavivaJ, WongR, CharestA (2009) The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer. Biochim Biophys Acta 1795: 37–52.

44. RikovaK, GuoA, ZengQ, PossematoA, YuJ, et al. (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131: 1190–1203.

45. CharestA, LaneK, McMahonK, ParkJ, PreisingerE, et al. (2003) Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21). Genes Chromosomes Cancer 37: 58–71.

46. GuTL, DengX, HuangF, TuckerM, CrosbyK, et al. (2011) Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS ONE 6: e15640 doi:10.1371/journal.pone.0015640.

47. ToguchidaJ, NakayamaT (2009) Molecular genetics of sarcomas: applications to diagnoses and therapy. Cancer Sci 100: 1573–1580.

48. YoungRJ, BrownNJ, ReedMW, HughesD, WollPJ (2010) Angiosarcoma. Lancet Oncol 11: 983–991.

49. ChmieleckiJ, PeiferM, VialeA, HutchinsonK, GiltnaneJ, et al. (2012) Systematic screen for tyrosine kinase rearrangements identifies a novel C6orf204-PDGFRB fusion in a patient with recurrent T-ALL and an associated myeloproliferative neoplasm. Genes Chromosomes Cancer 51: 54–65.

50. ApweilerR, Jesus MartinM, O'onovanC, MagraneM, Alam-FaruqueY, et al. (2012) Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res 40: D71–75.

51. CharestA, KheifetsV, ParkJ, LaneK, McMahonK, et al. (2003) Oncogenic targeting of an activated tyrosine kinase to the Golgi apparatus in a glioblastoma. Proc Natl Acad Sci U S A 100: 916–921.

52. SodaM, TakadaS, TakeuchiK, ChoiYL, EnomotoM, et al. (2008) A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 105: 19893–19897.

53. WestRB, NuytenDS, SubramanianS, NielsenTO, CorlessCL, et al. (2005) Determination of stromal signatures in breast carcinoma. PLoS Biol 3: e187 oi:10.1371/journal.pbio.0030187.

54. WestRB, RubinBP, MillerMA, SubramanianS, KaygusuzG, et al. (2006) A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci U S A 103: 690–695.

55. BeckAH, LeeCH, WittenDM, GleasonBC, EdrisB, et al. (2010) Discovery of molecular subtypes in leiomyosarcoma through integrative molecular profiling. Oncogene 29: 845–854.

56. WuC, OrozcoC, BoyerJ, LegliseM, GoodaleJ, et al. (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 10: R130.

57. SuAI, WiltshireT, BatalovS, LappH, ChingKA, et al. (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 101: 6062–6067.

58. LobodaA, NebozhynMV, WattersJW, BuserCA, ShawPM, et al. (2011) EMT is the dominant program in human colon cancer. BMC Med Genomics 4: 9.

59. KoorstraJB, HustinxSR, OfferhausGJ, MaitraA (2008) Pancreatic carcinogenesis. Pancreatology 8: 110–125.

60. DelattreO, ZucmanJ, PlougastelB, DesmazeC, MelotT, et al. (1992) Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 359: 162–165.

61. GeraldWL, RosaiJ, LadanyiM (1995) Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor. Proc Natl Acad Sci U S A 92: 1028–1032.

62. MartiniA, La StarzaR, JanssenH, Bilhou-NaberaC, CorveleynA, et al. (2002) Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia. Cancer Res 62: 5408–5412.

63. MolinaCA, FoulkesNS, LalliE, Sassone-CorsiP (1993) Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor. Cell 75: 875–886.

64. MasquilierD, FoulkesNS, MatteiMG, Sassone-CorsiP (1993) Human CREM gene: evolutionary conservation, chromosomal localization, and inducibility of the transcript. Cell Growth Differ 4: 931–937.

65. FoulkesNS, BorrelliE, Sassone-CorsiP (1991) CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription. Cell 64: 739–749.

66. HayetteS, TigaudI, Callet-BauchuE, FfrenchM, GazzoS, et al. (2003) In B-cell chronic lymphocytic leukemias, 7q21 translocations lead to overexpression of the CDK6 gene. Blood 102: 1549–1550.

67. RaffiniLJ, SlaterDJ, RappaportEF, Lo NigroL, CheungNK, et al. (2002) Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions of MLL translocations and identify complex translocation of MLL, AF-4, and CDK6. Proc Natl Acad Sci U S A 99: 4568–4573.

68. CorcoranMM, MouldSJ, OrchardJA, IbbotsonRE, ChapmanRM, et al. (1999) Dysregulation of cyclin dependent kinase 6 expression in splenic marginal zone lymphoma through chromosome 7q translocations. Oncogene 18: 6271–6277.

69. OhashiPS, MakTW, Van den ElsenP, YanagiY, YoshikaiY, et al. (1985) Reconstitution of an active surface T3/T-cell antigen receptor by DNA transfer. Nature 316: 606–609.

70. ArganiP, LuiMY, CouturierJ, BouvierR, FournetJC, et al. (2003) A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23). Oncogene 22: 5374–5378.

71. CoolsJ, WlodarskaI, SomersR, MentensN, PedeutourF, et al. (2002) Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes Chromosomes Cancer 34: 354–362.

72. GascoyneRD, LamantL, Martin-SuberoJI, LestouVS, HarrisNL, et al. (2003) ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. Blood 102: 2568–2573.

73. RobinsonDR, Kalyana-SundaramS, WuYM, ShankarS, CaoX, et al. (2011) Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat Med 17: 1646–1651.

74. BignerSH, HumphreyPA, WongAJ, VogelsteinB, MarkJ, et al. (1990) Characterization of the epidermal growth factor receptor in human glioma cell lines and xenografts. Cancer Res 50: 8017–8022.

75. StockhausenMT, BroholmH, VillingshojM, KirchhoffM, GerdesT, et al. (2011) Maintenance of EGFR and EGFRvIII expressions in an in vivo and in vitro model of human glioblastoma multiforme. Exp Cell Res 317: 1513–1526.

76. Del VecchioCA, GiacominiCP, VogelH, JensenKC, FlorioT, et al. (2012) EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms. Oncogene July 16 [Epub ahead of print].

77. CoolsJ, QuentmeierH, HuntlyBJ, MarynenP, GriffinJD, et al. (2004) The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood 103: 2802–2805.

78. CoolsJ, DeAngeloDJ, GotlibJ, StoverEH, LegareRD, et al. (2003) A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348: 1201–1214.

79. BergethonK, ShawAT, OuSH, KatayamaR, LovlyCM, et al. (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30: 863–870.

80. ShiffmanD, EllisSG, RowlandCM, MalloyMJ, LukeMM, et al. (2005) Identification of four gene variants associated with myocardial infarction. Am J Hum Genet 77: 596–605.

81. YamadaY, MetokiN, YoshidaH, SatohK, KatoK, et al. (2008) Genetic factors for ischemic and hemorrhagic stroke in Japanese individuals. Stroke 39: 2211–2218.

82. RabbittsTH (1994) Chromosomal translocations in human cancer. Nature 372: 143–149.

83. DeBerardinisRJ, LumJJ, HatzivassiliouG, ThompsonCB (2008) The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: 11–20.

84. NakanishiT (2007) Drug transporters as targets for cancer chemotherapy. Cancer Genomics Proteomics 4: 241–254.

85. ChappellWH, SteelmanLS, LongJM, KempfRC, AbramsSL, et al. (2011) Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2: 135–164.

86. McCubreyJA, SteelmanLS, AbramsSL, ChappellWH, RussoS, et al. (2009) Emerging Raf inhibitors. Expert Opin Emerg Drugs 14: 633–648.

87. BrennerJC, FengFY, HanS, PatelS, GoyalSV, et al. (2012) PARP-1 inhibition as a targeted strategy to treat Ewing's sarcoma. Cancer Res 72: 1608–1613.

88. HuMG, DeshpandeA, EnosM, MaoD, HindsEA, et al. (2009) A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis. Cancer Res 69: 810–818.

89. JanY, MatterM, PaiJT, ChenYL, PilchJ, et al. (2004) A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors. Cell 116: 751–762.

90. EdgarR, DomrachevM, LashAE (2002) Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30: 207–210.

91. LapointeJ, LiC, HigginsJP, van de RijnM, BairE, et al. (2004) Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci U S A 101: 811–816.

92. NowakG, HastieT, PollackJR, TibshiraniR (2011) A fused lasso latent feature model for analyzing multi-sample aCGH data. Biostatistics 12: 776–791.

93. BarretinaJ, CaponigroG, StranskyN, VenkatesanK, MargolinAA, et al. (2012) The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483: 603–607.

94. KimYH, GirardL, GiacominiCP, WangP, Hernandez-BoussardT, et al. (2006) Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification. Oncogene 25: 130–138.

95. Del VecchioCA, JensenKC, NittaRT, ShainAH, GiacominiCP, et al. (2012) Epidermal growth factor receptor variant III contributes to cancer stem cell phenotypes in invasive breast carcinoma. Cancer Res 72: 2657–2671.

96. HeisterkampN, MorrisC, SenderL, KnoppelE, UribeL, et al. (1990) Rearrangement of the human ABL oncogene in a glioblastoma. Cancer Res 50: 3429–3434.

97. UllrichA, CoussensL, HayflickJS, DullTJ, GrayA, et al. (1984) Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309: 418–425.

98. HuntsJH, ShimizuN, YamamotoT, ToyoshimaK, MerlinoGT, et al. (1985) Translocation chromosome 7 of A431 cells contains amplification and rearrangement of EGF receptor gene responsible for production of variant mRNA. Somat Cell Mol Genet 11: 477–484.