Relevance of Fusion Genes in Pediatric Cancers: Toward Precision Medicine
2017; Cell Press; Volume: 6; Linguagem: Inglês
10.1016/j.omtn.2017.01.005
ISSN2162-2531
AutoresCélia Dupain, Anne C. Harttrampf, Giorgia Urbinati, Birgit Geoerger, Liliane Massaad-Massade,
Tópico(s)Genetic factors in colorectal cancer
ResumoPediatric cancers differ from adult tumors, especially by their very low mutational rate. Therefore, their etiology could be explained in part by other oncogenic mechanisms such as chromosomal rearrangements, supporting the possible implication of fusion genes in the development of pediatric cancers. Fusion genes result from chromosomal rearrangements leading to the juxtaposition of two genes. Consequently, an abnormal activation of one or both genes is observed. The detection of fusion genes has generated great interest in basic cancer research and in the clinical setting, since these genes can lead to better comprehension of the biological mechanisms of tumorigenesis and they can also be used as therapeutic targets and diagnostic or prognostic biomarkers. In this review, we discuss the molecular mechanisms of fusion genes and their particularities in pediatric cancers, as well as their relevance in murine models and in the clinical setting. We also point out the difficulties encountered in the discovery of fusion genes. Finally, we discuss future perspectives and priorities for finding new innovative therapies in childhood cancer. Pediatric cancers differ from adult tumors, especially by their very low mutational rate. Therefore, their etiology could be explained in part by other oncogenic mechanisms such as chromosomal rearrangements, supporting the possible implication of fusion genes in the development of pediatric cancers. Fusion genes result from chromosomal rearrangements leading to the juxtaposition of two genes. Consequently, an abnormal activation of one or both genes is observed. The detection of fusion genes has generated great interest in basic cancer research and in the clinical setting, since these genes can lead to better comprehension of the biological mechanisms of tumorigenesis and they can also be used as therapeutic targets and diagnostic or prognostic biomarkers. In this review, we discuss the molecular mechanisms of fusion genes and their particularities in pediatric cancers, as well as their relevance in murine models and in the clinical setting. We also point out the difficulties encountered in the discovery of fusion genes. Finally, we discuss future perspectives and priorities for finding new innovative therapies in childhood cancer. Pediatric cancers represent 1% of all cancers1American Cancer Society (2016). Key statistics for childhood cancers. https://www.cancer.org/cancer/cancerinchildren/detailedguide/cancer-in-children-key-statistics.Google Scholar and comprise cancer cases diagnosed in children younger than 14 years2Bahadur G. Hindmarsh P. Age definitions, childhood and adolescent cancers in relation to reproductive issues.Hum. Reprod. 2000; 15: 227Crossref PubMed Google Scholar and adolescents and young adults aged 15–19 years.3Minnesota Department of Health (2016). Childhood cancers: facts and figures. https://apps.health.state.mn.us/mndata/cancer_child#childbraincancer_year.Google Scholar Pediatric cancers include more than 60 different types of cancer derived from different tissues. More than 250,000 cases are diagnosed worldwide each year among children and adolescents younger than 20 years (http://www.childhoodcancerinternational.org). Although 80% of pediatric patients reach long-term remission after treatment, 20% die from recurrence of the malignancy; therefore, more therapeutic targets are needed to improve survival rates.1American Cancer Society (2016). Key statistics for childhood cancers. https://www.cancer.org/cancer/cancerinchildren/detailedguide/cancer-in-children-key-statistics.Google Scholar Moreover, current treatments are based on multimodal aggressive chemotherapies, and it is well known that antineoplastic treatments have long-term side effects that could impact patients' quality of life.4Fidler M.M. Reulen R.C. Winter D.L. Kelly J. Jenkinson H.C. Skinner R. Frobisher C. Hawkins M.M. British Childhood Cancer Survivor Study Steering GroupLong term cause specific mortality among 34 489 five year survivors of childhood cancer in Great Britain: population based cohort study.BMJ. 2016; 354: i4351Crossref PubMed Google Scholar Pediatric cancers differ from adult cancers. In fact, most pediatric cancers arise from embryonal rather than epithelial cells;5Marshall G.M. Carter D.R. Cheung B.B. Liu T. Mateos M.K. Meyerowitz J.G. Weiss W.A. The prenatal origins of cancer.Nat. Rev. Cancer. 2014; 14: 277-289Crossref PubMed Scopus (106) Google Scholar consequently, the etiology of pediatric cancers is different. Zhang et al.6Zhang J. Walsh M.F. Wu G. Edmonson M.N. Gruber T.A. Easton J. Hedges D. Ma X. Zhou X. Yergeau D.A. et al.Germline mutations in predisposition genes in pediatric cancer.N. Engl. J. Med. 2015; 373: 2336-2346Crossref PubMed Scopus (338) Google Scholar previously reported that 8%–10% of pediatric cancers are associated with germline alterations leading to a cancer predisposition (Table 1). The involvement of environmental factors in childhood cancer etiology is still discussed, but there is clearly a lower implication of exogenous toxic effects in children than in adults (e.g., smoking, alcohol consumption, sun exposure, and overweight and sedentary lifestyle). Very few environmental factors have been related to pediatric cancers to date: ionizing radiation and electromagnetic fields are some of the effects that remain a source of controversy, whereas some chemicals such as dioxin, trichloroethane, pesticides, solvents, metals, petroleum products, boron, and pollution have been associated with specific cancer types.7Kaatsch P. Epidemiology of childhood cancer.Cancer Treat. Rev. 2010; 36: 277-285Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar, 8Kupfer, G.M. (2015). Childhood cancer epidemiology: overview, tools of study, cancer incidence. http://emedicine.medscape.com/article/989841-overview.Google Scholar Other factors such as epigenetics and immune system deregulation have also been identified as being responsible for tumorigenesis.9Huether R. Dong L. Chen X. Wu G. Parker M. Wei L. Ma J. Edmonson M.N. Hedlund E.K. Rusch M.C. et al.The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes.Nat. Commun. 2014; 5: 3630Crossref PubMed Google Scholar, 10Orentas R.J. Lee D.W. Mackall C. Immunotherapy targets in pediatric cancer.Front. Oncol. 2012; 2: 3PubMed Google ScholarTable 1Syndromes of Genetic Predisposition Found among Children with Cancer and the Corresponding Affected GenesGenetic PredispositionAffected GeneaChildren's Health and the Environment, WHO Training Package for the Health Sector (World Health Organization, http://www.who.int/ceh).Li-Fraumeni syndromeTP53/CHK2/SNF5Familial Wilms tumorFTW1/2Familial retinoblastomaRB1Fanconi anemiaFANCAIgA deficiencyIGAD1Blood syndromeBLMWiskott-Aldrich syndromeWASAtaxia telangiectasiaATMFamilial adenomatous polyposisAPCHereditary non-polyposis colon cancerMSH2/MLH1/PMS2Tuberous sclerosisTSC1/2Beckwith-Wiedemann syndromeComplexXeroderma pigmentosumERCC2a Children's Health and the Environment, WHO Training Package for the Health Sector (World Health Organization, http://www.who.int/ceh). Open table in a new tab Vogelstein et al.11Vogelstein B. Papadopoulos N. Velculescu V.E. Zhou S. Diaz Jr., L.A. Kinzler K.W. Cancer genome landscapes.Science. 2013; 339: 1546-1558Crossref PubMed Scopus (3632) Google Scholar highlighted that pediatric cancers usually harbor fewer genetic mutations than adult cancers. They explained that the lower mutation rate found in pediatric cancers may be due to the embryonal origin of these cancers, which did not have enough time to renew. As a consequence, the tumors harbor very few mutations at the basal state.11Vogelstein B. Papadopoulos N. Velculescu V.E. Zhou S. Diaz Jr., L.A. Kinzler K.W. Cancer genome landscapes.Science. 2013; 339: 1546-1558Crossref PubMed Scopus (3632) Google Scholar These differences in mutation patterns could also be explained in part by the difference in cancer initiation, such as the implication of exogenous toxic effects. A possible hypothesis of their etiology could be the presence of chromosome rearrangements, which is one of the first mechanisms described to be responsible for carcinogenesis.12Duesberg P.H. Cancer genes generated by rare chromosomal rearrangements rather than activation of oncogenes.Med. Oncol. Tumor Pharmacother. 1987; 4: 163-175Crossref PubMed Scopus (4) Google Scholar These rearrangements can lead, in some cases, to fusion genes, which are the juxtaposition of two previously separate genes localized on the same (intra-chromosomal) or two different (inter-chromosomal) chromosomes. This event can activate proto-oncogenes or inactivate tumor suppressor genes. It has also been shown in adult cancers that some tumors with driving fusions have a much lower mutational burden compared to tumors without fusions.13Yoshihara K. Wang Q. Torres-Garcia W. Zheng S. Vegesna R. Kim H. Verhaak R.G. The landscape and therapeutic relevance of cancer-associated transcript fusions.Oncogene. 2015; 34: 4845-4854Crossref PubMed Scopus (191) Google Scholar Thus, pediatric cancers appear to be the consequence of chromosomal rearrangements rather than mutation events. We should keep in mind that a recurrence of alterations (mutations and copy-number alterations) of genes involved in embryogenesis14Walz A.L. Ooms A. Gadd S. Gerhard D.S. Smith M.A. Guidry Auvil J.M. Meerzaman D. Chen Q.R. Hsu C.H. Yan C. et al.Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors.Cancer Cell. 2015; 27: 286-297Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar and epigenetic regulation are also described in pediatric cancers9Huether R. Dong L. Chen X. Wu G. Parker M. Wei L. Ma J. Edmonson M.N. Hedlund E.K. Rusch M.C. et al.The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes.Nat. Commun. 2014; 5: 3630Crossref PubMed Google Scholar but will not be discussed here. In this review, we describe recent molecular knowledge on fusion genes in pediatric cancers. We then outline the potential therapeutic utility of fusion genes, their relevance in murine models, and we describe recent findings in the clinical setting as well as challenges associated with their discovery. Fusion genes were primarily discovered in leukemia and other hematological diseases. In 1962, Nowell15Nowell P.C. The minute chromosome (Phl) in chronic granulocytic leukemia.Blut. 1962; 8: 65-66Crossref PubMed Scopus (0) Google Scholar described the first specific chromosomal rearrangement in chronic myeloid leukemia (CML). In 1973, Rowley16Rowley J.D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining.Nature. 1973; 243: 290-293Crossref PubMed Google Scholar highlighted the existence of a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9q; 22q), named the "Philadelphia chromosome." Twenty years later in the early 1980s, molecular studies of the translocation revealed a fusion between the 3′ part of the ABL1 gene in chromosome 9 and the 5′ part of the BCR1 gene in chromosome 22.17de Klein A. van Kessel A.G. Grosveld G. Bartram C.R. Hagemeijer A. Bootsma D. Spurr N.K. Heisterkamp N. Groffen J. Stephenson J.R. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia.Nature. 1982; 300: 765-767Crossref PubMed Scopus (976) Google Scholar This translocation resulting in BCR-ABL was one of the first specific alterations found in human neoplasm. Ten years later, a tyrosine kinase inhibitor (TKI) targeting BCR-ABL, imatinib mesylate (Glivec; Novartis), was discovered and approved by the Food and Drug Administration (FDA) in 2001 as a cancer treatment for CML.18Basel, N. 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Kuefer R. et al.Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer.Science. 2005; 310: 644-648Crossref PubMed Scopus (2670) Google Scholar, 21Ju Y.S. Lee W.-C. Shin J.-Y. Lee S. Bleazard T. Won J.-K. Kim Y.T. Kim J.I. Kang J.H. Seo J.S. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing.Genome Res. 2012; 22: 436-445Crossref PubMed Scopus (316) Google Scholar It should be noted that most of the studies and discoveries to date were made among adult patients; nevertheless, some pediatric cancers have been described to also harbor fusion genes that are involved in patients' diagnosis and/or targeted treatments (Table 2). However, more explorations are needed to not only identify new targets but also to understand the function of fusion genes and their correlation to tumor initiation and progression.22Mitelman F. Johansson B. Mertens F. 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