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Abstract

Despite the success of treating childhood cancers with cytotoxic agents, novel therapeutic strategies are required to achieve the next leap in cure rates. A promising avenue may be to target the origin of childhood cancers. Here, we review recent advances in tracing the origins of pediatric tumors. Cancer-to-normal cell comparisons by single-cell mRNA sequencing reveal the fetal state of cancer cells, as well as their cell of origin. Recent phylogenetic analyses have uncovered large tissue-resident precursor clones to childhood cancers, which already possess key genomic alterations leading to tumor formation. Both the transcriptional fetalness and genomic status of the premalignant tissue bed provide further avenues for targeted therapy. Overall, these advances begin to describe the precise origins of pediatric tumors and pave the way for novel methods in detecting, treating, and perhaps even preventing childhood cancers.

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/content/journals/10.1146/annurev-cancerbio-070620-091632
2022-04-11
2024-03-28
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Literature Cited

  1. Aldridge S, Teichmann SA. 2020. Single cell transcriptomics comes of age. Nat. Commun. 11:4307
    [Google Scholar]
  2. Behjati S, Gilbertson RJ, Pfister SM. 2021. Maturation block in childhood cancer. Cancer Discov 11:542–44
    [Google Scholar]
  3. Behjati S, Huch M, van Boxtel R, Karthaus W, Wedge DC et al. 2014. Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature 513:422–25
    [Google Scholar]
  4. Behjati S, Lindsay S, Teichmann SA, Haniffa M. 2018. Mapping human development at single-cell resolution. Development 145:3dev152561
    [Google Scholar]
  5. Bhakta N, Liu Q, Ness KK, Baassiri M, Eissa H et al. 2017. The cumulative burden of surviving childhood cancer: an initial report from the St. Jude Lifetime Cohort Study (SJLIFE). Lancet 390:2569–82
    [Google Scholar]
  6. Bizzotto S, Dou Y, Ganz J, Doan RN, Kwon M et al. 2021. Landmarks of human embryonic development inscribed in somatic mutations. Science 371:1249–53
    [Google Scholar]
  7. Breslow N, Beckwith JB, Ciol M, Sharples K 1988. Age distribution of Wilms' tumor: report from the National Wilms' Tumor Study. Cancer Res 48:1653–57
    [Google Scholar]
  8. Breuss MW, Yang X, Antaki D, Schlachetzki JCM, Lana AJ et al. 2020. Somatic mosaicism in the mature brain reveals clonal cellular distributions during cortical development. bioRxiv 2020.08.10.244814. https://doi.org/10.1101/2020.08.10.244814
    [Crossref]
  9. Chapman MS, Ranzoni AM, Myers B, Williams N, Coorens THH et al. 2021. Lineage tracing of human embryonic development and foetal haematopoiesis through somatic mutations. Nature 595:786585–90
    [Google Scholar]
  10. Cheng J, Vanneste E, Konings P, Voet T, Vermeesch JR, Moreau Y. 2011. Single-cell copy number variation detection. Genome Biol 12:R80
    [Google Scholar]
  11. Coorens THH, Farndon SJ, Mitchell TJ, Jain N, Lee S et al. 2020. Lineage-independent tumors in bilateral neuroblastoma. N. Engl. J. Med. 383:1860–65
    [Google Scholar]
  12. Coorens THH, Moore L, Robinson PS, Sanghvi R, Christopher J et al. 2021a. Extensive phylogenies of human development inferred from somatic mutations. Nature 597:387–92
    [Google Scholar]
  13. Coorens THH, Oliver TRW, Sanghvi R, Sovio U, Cook E et al. 2021b. Inherent mosaicism and extensive mutation of human placentas. Nature 592:80–85
    [Google Scholar]
  14. Coorens THH, Treger TD, Al-Saadi R, Moore L, Tran MGB et al. 2019. Embryonal precursors of Wilms tumor. Science 366:1247–51
    [Google Scholar]
  15. Custers L, Khabirova E, Coorens THH, Oliver TRW, Calandrini C et al. 2021. Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours. Nat. Commun. 12:1407
    [Google Scholar]
  16. Dong R, Yang R, Zhan Y, Lai HD, Ye CJ et al. 2020. Single-cell characterization of malignant phenotypes and developmental trajectories of adrenal neuroblastoma. Cancer Cell 38:716–33.e6
    [Google Scholar]
  17. Downing JR, Shannon KM. 2002. Acute leukemia: a pediatric perspective. Cancer Cell 2:437–45
    [Google Scholar]
  18. Ellis P, Moore L, Sanders MA, Butler TM, Brunner SF et al. 2021. Reliable detection of somatic mutations in solid tissues by laser-capture microdissection and low-input DNA sequencing. Nat. Protoc. 16:841–71
    [Google Scholar]
  19. Fan J, Lee HO, Lee S, Ryu DE, Lee S et al. 2018. Linking transcriptional and genetic tumor heterogeneity through allele analysis of single-cell RNA-seq data. Genome. Res. 28:1217–27
    [Google Scholar]
  20. Fasching L, Jang Y, Tomasi S, Schreiner J, Tomasini L et al. 2021. Early developmental asymmetries in cell lineage trees in living individuals. Science 371:1245–48
    [Google Scholar]
  21. Feinberg AP, Ohlsson R, Henikoff S 2006. The epigenetic progenitor origin of human cancer. Nat. Rev. Genet. 7:21–33
    [Google Scholar]
  22. Filbin MG, Monje M. 2019. Developmental origins and emerging therapeutic opportunities for childhood cancer. Nat. Med. 25:367–76
    [Google Scholar]
  23. Filbin MG, Tirosh I, Hovestadt V, Shaw ML, Escalante LE et al. 2018. Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq. Science 360:331–35
    [Google Scholar]
  24. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS et al. 2010. Subtypes of medulloblastoma have distinct developmental origins. Nature 468:1095–99
    [Google Scholar]
  25. Gojo J, Englinger B, Jiang L, Hubner JM, Shaw ML et al. 2020. Single-Cell RNA-seq reveals cellular hierarchies and impaired developmental trajectories in pediatric ependymoma. Cancer Cell 38:44–59.e9
    [Google Scholar]
  26. Greaves M. 2018. A causal mechanism for childhood acute lymphoblastic leukaemia. Nat. Rev. Cancer 18:471–84
    [Google Scholar]
  27. Hirsch TZ, Pilet J, Morcrette G, Roehrig A, Monteiro BJ et al. 2021. Integrated genomic analysis identifies driver genes and cisplatin-resistant progenitor phenotype in pediatric liver cancer. Cancer Discov 11:2524–43
    [Google Scholar]
  28. Hovestadt V, Smith KS, Bihannic L, Filbin MG, Shaw ML et al. 2019. Resolving medulloblastoma cellular architecture by single-cell genomics. Nature 572:74–79
    [Google Scholar]
  29. Inaba H, Mullighan CG. 2020. Pediatric acute lymphoblastic leukemia. Haematologica 105:2524–39
    [Google Scholar]
  30. Jansky S, Sharma AK, Korber V, Quintero A, Toprak UH et al. 2021. Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma. Nat. Genet. 53:683–93
    [Google Scholar]
  31. Jessa S, Blanchet-Cohen A, Krug B, Vladoiu M, Coutelier M et al. 2019. Stalled developmental programs at the root of pediatric brain tumors. Nat. Genet. 51:1702–13
    [Google Scholar]
  32. Ju YS, Martincorena I, Gerstung M, Petljak M, Alexandrov LB et al. 2017. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature 543:714–18
    [Google Scholar]
  33. Kameneva P, Artemov AV, Kastriti ME, Faure L, Olsen TK et al. 2021. Single-cell transcriptomics of human embryos identifies multiple sympathoblast lineages with potential implications for neuroblastoma origin. Nat. Genet. 53:694–706
    [Google Scholar]
  34. Kildisiute G, Kholosy WM, Young MD, Roberts K, Elmentaite R et al. 2021. Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell. Sci. Adv. 7:eabd3311
    [Google Scholar]
  35. Laks E, McPherson A, Zahn H, Lai D, Steif A et al. 2019. Clonal decomposition and DNA replication states defined by scaled single-cell genome sequencing. Cell 179:1207–21.e22
    [Google Scholar]
  36. Lee-Six H, Obro NF, Shepherd MS, Grossmann S, Dawson K et al. 2018. Population dynamics of normal human blood inferred from somatic mutations. Nature 561:473–78
    [Google Scholar]
  37. Lee-Six H, Olafsson S, Ellis P, Osborne RJ, Sanders MA et al. 2019. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574:532–37
    [Google Scholar]
  38. Lodato MA, Rodin RE, Bohrson CL, Coulter ME, Barton AR et al. 2018. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359:555–59
    [Google Scholar]
  39. Lodato MA, Woodworth MB, Lee S, Evrony GD, Mehta BK et al. 2015. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350:94–98
    [Google Scholar]
  40. Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J et al. 2017. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32:520–37.e5
    [Google Scholar]
  41. Margol AS, Judkins AR. 2014. Pathology and diagnosis of SMARCB1-deficient tumors. Cancer Genet 207:358–64
    [Google Scholar]
  42. McCarthy DJ, Rostom R, Huang Y, Kunz DJ, Danecek P et al. 2020. Cardelino: computational integration of somatic clonal substructure and single-cell transcriptomes. Nat. Methods 17:414–21
    [Google Scholar]
  43. Miller DR. 2006. A tribute to Sidney Farber—the father of modern chemotherapy. Br. J. Haematol. 134:20–26
    [Google Scholar]
  44. Moore L, Cagan A, Coorens THH, Neville MDC, Sanghvi R et al. 2021. The mutational landscape of human somatic and germline cells. Nature 597:381–86
    [Google Scholar]
  45. Moore L, Leongamornlert D, Coorens THH, Sanders MA, Ellis P et al. 2020. The mutational landscape of normal human endometrial epithelium. Nature 580:640–46
    [Google Scholar]
  46. Mora J, Cheung NK, Juan G, Illei P, Cheung I et al. 2001. Neuroblastic and Schwannian stromal cells of neuroblastoma are derived from a tumoral progenitor cell. Cancer Res 61:6892–98
    [Google Scholar]
  47. Neftel C, Laffy J, Filbin MG, Hara T, Shore ME et al. 2019. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 178:835–49.e21
    [Google Scholar]
  48. Olafsson S, McIntyre RE, Coorens T, Butler T, Jung H et al. 2020. Somatic evolution in non-neoplastic IBD-affected colon. Cell 182:672–84.e11
    [Google Scholar]
  49. Park JA, Cheung NV. 2020. Targets and antibody formats for immunotherapy of neuroblastoma. J. Clin. Oncol. 38:1836–48
    [Google Scholar]
  50. Park S, Mali NM, Kim R, Choi J-W, Lee J et al. 2021. Clonal dynamics in early human embryogenesis inferred from somatic mutation. Nature 597:393–97
    [Google Scholar]
  51. Pizzo PA, Poplack DG, Adamson PC, Blaney SM, Helman L. 2016. Principles and Practice of Pediatric Oncology Philadelphia: Wolters Kluwer
  52. Robinson PS, Coorens THH, Palles C, Mitchell E, Abascal F et al. 2021. Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nat. Genet. 53:1434–42
    [Google Scholar]
  53. Rozenblatt-Rosen O, Stubbington MJT, Regev A, Teichmann SA 2017. The Human Cell Atlas: from vision to reality. Nature 550:451–53
    [Google Scholar]
  54. Straathof K, Flutter B, Wallace R, Jain N, Loka T et al. 2020. Antitumor activity without on-target off-tumor toxicity of GD2–chimeric antigen receptor T cells in patients with neuroblastoma. Sci. Transl. Med. 12:571eabd6169
    [Google Scholar]
  55. Stratton MR, Campbell PJ, Futreal PA. 2009. The cancer genome. Nature 458:719–24
    [Google Scholar]
  56. Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP et al. 2016. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature 539:309–13
    [Google Scholar]
  57. van Noesel MM. 2012. Neuroblastoma stage 4S: a multifocal stem-cell disease of the developing neural crest. Lancet Oncol 13:229–30
    [Google Scholar]
  58. Wilms M. 1899. Die Mischgeschwülste der Niere Leipzig, Ger: Verlag Arthur Georgi
  59. Young MD, Mitchell TJ, Custers L, Margaritis T, Morales-Rodriguez F et al. 2021. Single cell derived mRNA signals across human kidney tumors. Nat. Commun. 12:3896
    [Google Scholar]
  60. Young MD, Mitchell TJ, Vieira Braga FA, Tran MGB, Stewart BJ et al. 2018. Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science 361:594–99
    [Google Scholar]
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