Driver Fusions and Their Implications in the Development and Treatment of Human Cancers

SUMMARY Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy.

[1]  Morten Nielsen,et al.  Gapped sequence alignment using artificial neural networks: application to the MHC class I system , 2016, Bioinform..

[2]  S. Gabriel,et al.  Discovery and saturation analysis of cancer genes across 21 tumor types , 2014, Nature.

[3]  David T. W. Jones,et al.  Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. , 2008, Cancer research.

[4]  Benjamin J. Raphael,et al.  Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. , 2013, The New England journal of medicine.

[5]  Li Ding,et al.  Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines. , 2018, Cell systems.

[6]  Z. Weng,et al.  High-Resolution Mapping and Characterization of Open Chromatin across the Genome , 2008, Cell.

[7]  G. Mills,et al.  Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer. , 2017, Cancer research.

[8]  David Cameron,et al.  2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial , 2007, The Lancet.

[9]  Nicolas Stransky,et al.  The landscape of kinase fusions in cancer , 2014, Nature Communications.

[10]  Arul M. Chinnaiyan,et al.  Landscape of gene fusions in epithelial cancers: seq and ye shall find , 2015, Genome Medicine.

[11]  O. Hantschel.  Structure, regulation, signaling, and targeting of abl kinases in cancer. , 2012, Genes & cancer.

[12]  Timothy L. Tickle,et al.  STAR-Fusion: Fast and Accurate Fusion Transcript Detection from RNA-Seq , 2017, bioRxiv.

[13]  Yanjun Qi,et al.  Recurrent chimeric fusion RNAs in non-cancer tissues and cells , 2016, Nucleic acids research.

[14]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[15]  A. Iavarone,et al.  FGFR-TACC gene fusions in human glioma , 2016, Neuro-oncology.

[16]  Jonathan R. Pollack,et al.  Breakpoint Analysis of Transcriptional and Genomic Profiles Uncovers Novel Gene Fusions Spanning Multiple Human Cancer Types , 2013, PLoS genetics.

[17]  T. Holyoake,et al.  Targeting survival pathways in chronic myeloid leukaemia stem cells , 2013, British journal of pharmacology.

[18]  Li Ding,et al.  Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. , 2013, Cell reports.

[19]  M. Konantz,et al.  Targeting DDR2 in head and neck squamous cell carcinoma with dasatinib , 2016, International journal of cancer.

[20]  Ming Tang,et al.  TumorFusions: an integrative resource for cancer-associated transcript fusions , 2017, Nucleic Acids Res..

[21]  D. Brat,et al.  Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma , 2012, Science.

[22]  Kristian Cibulskis,et al.  Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion , 2011, Nature Genetics.

[23]  P. Sethupathy,et al.  Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma , 2017, Scientific Reports.

[24]  Aleix Prat Aparicio.  Comprehensive molecular portraits of human breast tumours , 2012 .

[25]  Steven J. M. Jones,et al.  Integrated genomic characterization of endometrial carcinoma , 2013, Nature.

[26]  A. Kohlmann,et al.  AML with CBFB–MYH11 rearrangement demonstrate RAS pathway alterations in 92% of all cases including a high frequency of NF1 deletions , 2010, Leukemia.

[27]  G. Coukos,et al.  Neoantigen-based cancer immunotherapy. , 2016, Annals of translational medicine.

[28]  Benjamin J. Raphael,et al.  Integrated Analysis of Germline and Somatic Variants in Ovarian Cancer , 2014, Nature Communications.

[29]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[30]  Gabor T. Marth,et al.  Novel somatic and germline mutations in intracranial germ cell tumours , 2014, Nature.

[31]  The Cancer Genome Atlas Research Network,et al.  Comprehensive molecular characterization of urothelial bladder carcinoma , 2014, Nature.

[32]  Bin Zhang,et al.  PhosphoSitePlus, 2014: mutations, PTMs and recalibrations , 2014, Nucleic Acids Res..

[33]  K. Kinzler,et al.  Cancer Genome Landscapes , 2013, Science.

[34]  A. Services,et al.  Integrated genomic and molecular characterization of cervical cancer. , 2017 .

[35]  David L. Marron,et al.  Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations , 2017, Nature Communications.

[36]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[37]  Daniela Cilloni,et al.  Molecular Pathways: BCR-ABL , 2011, Clinical Cancer Research.

[38]  Benjamin J. Raphael,et al.  Mutational landscape and significance across 12 major cancer types , 2013, Nature.

[39]  Matthew A. Wyczalkowski,et al.  Divergent viral presentation among human tumors and adjacent normal tissues , 2016, Scientific Reports.

[40]  Sanghyuk Lee,et al.  ChimerDB 3.0: an enhanced database for fusion genes from cancer transcriptome and literature data mining , 2016, Nucleic Acids Res..

[41]  Alberto Magi,et al.  Discovering chimeric transcripts in paired-end RNA-seq data by using EricScript , 2012, Bioinform..

[42]  Steven J. M. Jones,et al.  Integrated genomic and molecular characterization of cervical cancer , 2017, Nature.

[43]  R. Ren,et al.  Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia , 2005, Nature Reviews Cancer.

[44]  D. Landau,et al.  Genomic complexity of multiple myeloma and its clinical implications , 2017, Nature Reviews Clinical Oncology.

[45]  Francesca Demichelis,et al.  Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma , 2010, Nature Medicine.

[46]  C. Gissi,et al.  Untranslated regions of mRNAs , 2002, Genome Biology.

[47]  Olivier Elemento,et al.  AGFusion: annotate and visualize gene fusions , 2016, bioRxiv.

[48]  P. Jordan,et al.  Emerging roles for WNK kinases in cancer , 2010, Cellular and Molecular Life Sciences.

[49]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of urothelial bladder carcinoma , 2014, Nature.

[50]  Steven J. M. Jones,et al.  Comprehensive Characterization of Cancer Driver Genes and Mutations , 2018, Cell.