Genetic predisposition and chromosome instability in neuroblastoma

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Neuroblastoma (NB) is a pediatric tumor of embryonic origin. About 1–2% of all NBs are familial cases, and genetic predisposition is suspected for the remaining cases. During the last decade, genome-wide association studies (GWAS) and high-throughput sequencing approaches have been used to identify associations among common and rare genetic variants and NB risk. Substantial data has been produced by large patient cohorts that implicate various genes in NB tumorigenesis, such as CASC15, BARD1, CHEK2, LMO1, LIN28B, AXIN2, BRCA1, TP53, SMARCA4, and CDK1NB. NB, as well as other pediatric cancers, has few recurrent mutations but several copy number variations (CNVs). Almost all NBs show both numerical and structural CNVs. The proportion between numerical and structural CNVs differs between localized and metastatic tumors, with a greater prevalence of structural CNVs in metastatic NB. This genomic chaos frequently identified in NBs suggests that chromosome instability (CIN) could be one of the major actors in NB oncogenesis. Interestingly, many NB-predisposing variants occur in genes involved in the control of genome stability, mitosis, and normal chromosome separation. Here, we discuss the relationship between genetic predisposition and CIN in NB.

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Chromosome instability


Genome-wide association studies


Next generation sequencing


Single nucleotide polymorphisms


Neural crest cells


Copy number variations


Hirschsprung disease


Congenital central hypoventilation syndrome


Long noncoding RNA


Microarray-comparative genomic hybridization


  1. 1.

    Delloye-Bourgeois, C., & Castellani, V. (2019). Hijacking of embryonic programs by neural crest-derived neuroblastoma: from physiological migration to metastatic dissemination. Frontiers in Molecular Neuroscience, 12, 52.

  2. 2.

    Luksch, R., Castellani, M. R., Collini, P., De Bernardi, B., Conte, M., Gambini, C., et al. (2016). Neuroblastoma (peripheral neuroblastic tumours). Critical Reviews in Oncology/Hematology, 107, 163–181.

  3. 3.

    Capasso, M., & Diskin, S. J. (2010). Genetics and genomics of neuroblastoma. Cancer Treatment and Research, 155, 65–84.

  4. 4.

    Russo, R., Cimmino, F., Pezone, L., Manna, F., Avitabile, M., Langella, C., Koster, J., Casale, F., Raia, M., Viola, G., Fischer, M., Iolascon, A., & Capasso, M. (2017). Kinome expression profiling of human neuroblastoma tumors identifies potential drug targets for ultra high-risk patients. Carcinogenesis, 38(10), 1011–1020.

  5. 5.

    Formicola, D., Petrosino, G., Lasorsa, V. A., Pignataro, P., Cimmino, F., Vetrella, S., Longo, L., Tonini, G. P., Oberthuer, A., Iolascon, A., Fischer, M., & Capasso, M. (2016). An 18 gene expression-based score classifier predicts the clinical outcome in stage 4 neuroblastoma. Journal of Translational Medicine, 14(1), 142–149.

  6. 6.

    Barbieri, E., De Preter, K., Capasso, M., Johansson, P., Man, T. K., Chen, Z., et al. (2013). A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. PLoS One, 8(11), e79843.

  7. 7.

    Grobner, S. N., Worst, B. C., Weischenfeldt, J., Buchhalter, I., Kleinheinz, K., Rudneva, V. A., et al. (2018). The landscape of genomic alterations across childhood cancers. Nature, 555(7696), 321–327.

  8. 8.

    Zhang, J., Walsh, M. F., Wu, G., Edmonson, M. N., Gruber, T. A., Easton, J., Hedges, D., Ma, X., Zhou, X., Yergeau, D. A., Wilkinson, M. R., Vadodaria, B., Chen, X., McGee, R., Hines-Dowell, S., Nuccio, R., Quinn, E., Shurtleff, S. A., Rusch, M., Patel, A., Becksfort, J. B., Wang, S., Weaver, M. S., Ding, L., Mardis, E. R., Wilson, R. K., Gajjar, A., Ellison, D. W., Pappo, A. S., Pui, C. H., Nichols, K. E., & Downing, J. R. (2015). Germline mutations in predisposition genes in pediatric cancer. The New England Journal of Medicine, 373(24), 2336–2346.

  9. 9.

    Trochet, D., Bourdeaut, F., Janoueix-Lerosey, I., Deville, A., de Pontual, L., Schleiermacher, G., Coze, C., Philip, N., Frébourg, T., Munnich, A., Lyonnet, S., Delattre, O., & Amiel, J. (2004). Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma. American Journal of Human Genetics, 74(4), 761–764.

  10. 10.

    Perri, P., Bachetti, T., Longo, L., Matera, I., Seri, M., Tonini, G. P., & Ceccherini, I. (2005). PHOX2B mutations and genetic predisposition to neuroblastoma. Oncogene, 24(18), 3050–3053.

  11. 11.

    Rohrer, T., Trachsel, D., Engelcke, G., & Hammer, J. (2002). Congenital central hypoventilation syndrome associated with Hirschsprung’s disease and neuroblastoma: case of multiple neurocristopathies. Pediatric Pulmonology, 33(1), 71–76.

  12. 12.

    Amiel, J., Laudier, B., Attie-Bitach, T., Trang, H., de Pontual, L., Gener, B., et al. (2003). Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nature Genetics, 33(4), 459–461.

  13. 13.

    Pattyn, A., Morin, X., Cremer, H., Goridis, C., & Brunet, J. F. (1999). The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives. Nature, 399(6734), 366–370.

  14. 14.

    Mosse, Y. P., Laudenslager, M., Khazi, D., Carlisle, A. J., Winter, C. L., Rappaport, E., & Maris, J. M. (2004). Germline PHOX2B mutation in hereditary neuroblastoma. American Journal of Human Genetics, 75(4), 727–730.

  15. 15.

    Raabe, E. H., Laudenslager, M., Winter, C., Wasserman, N., Cole, K., LaQuaglia, M., et al. (2008). Prevalence and functional consequence of PHOX2B mutations in neuroblastoma. Oncogene, 27(4), 469–476.

  16. 16.

    van Limpt, V., Schramm, A., van Lakeman, A., Sluis, P., Chan, A., van Noesel, M., et al. (2004). The Phox2B homeobox gene is mutated in sporadic neuroblastomas. Oncogene, 23(57), 9280–9288.

  17. 17.

    Serra, A., Haberle, B., Konig, I. R., Kappler, R., Suttorp, M., Schackert, H. K., et al. (2008). Rare occurrence of PHOX2b mutations in sporadic neuroblastomas. Journal of Pediatric Hematology/Oncology, 30(10), 728–732.

  18. 18.

    Bachetti, T., & Ceccherini, I. (2019). Causative and common PHOX2B variants define a broad phenotypic spectrum. Clinical Genetics.

  19. 19.

    Pei, D., Luther, W., Wang, W., Paw, B. H., Stewart, R. A., & George, R. E. (2013). Distinct neuroblastoma-associated alterations of PHOX2B impair sympathetic neuronal differentiation in zebrafish models. PLoS Genetics, 9(6), e1003533.

  20. 20.

    Reiff, T., Tsarovina, K., Majdazari, A., Schmidt, M., del Pino, I., & Rohrer, H. (2010). Neuroblastoma phox2b variants stimulate proliferation and dedifferentiation of immature sympathetic neurons. The Journal of Neuroscience, 30(3), 905–915.

  21. 21.

    van Limpt, V., Chan, A., Schramm, A., Eggert, A., & Versteeg, R. (2005). Phox2B mutations and the Delta-Notch pathway in neuroblastoma. Cancer Letters, 228(1–2), 59–63.

  22. 22.

    Revet, I., Huizenga, G., Chan, A., Koster, J., Volckmann, R., van Sluis, P., Øra, I., Versteeg, R., & Geerts, D. (2008). The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma. Experimental Cell Research, 314(4), 707–719.

  23. 23.

    Boeva, V., Louis-Brennetot, C., Peltier, A., Durand, S., Pierre-Eugene, C., Raynal, V., et al. (2017). Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries. Nature Genetics, 49(9), 1408–1413.

  24. 24.

    Longo, L., Panza, E., Schena, F., Seri, M., Devoto, M., Romeo, G., Bini, C., Pappalardo, G., Tonini, G. P., & Perri, P. (2007). Genetic predisposition to familial neuroblastoma: identification of two novel genomic regions at 2p and 12p. Human Heredity, 63(3–4), 205–211.

  25. 25.

    Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., et al. (2008). Identification of ALK as a major familial neuroblastoma predisposition gene. Nature, 455(7215), 930–935.

  26. 26.

    Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., & Ogawa, S. (2008). Oncogenic mutations of ALK kinase in neuroblastoma. Nature, 455(7215), 971–974.

  27. 27.

    Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., et al. (2008). Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature, 455(7215), 967–970.

  28. 28.

    George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther 2nd, W., Zhang, J., et al. (2008). Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature, 455(7215), 975–978.

  29. 29.

    Bresler, S. C., Weiser, D. A., Huwe, P. J., Park, J. H., Krytska, K., Ryles, H., Laudenslager, M., Rappaport, E. F., Wood, A. C., McGrady, P., Hogarty, M. D., London, W. B., Radhakrishnan, R., Lemmon, M. A., & Mossé, Y. P. (2014). ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell, 26(5), 682–694.

  30. 30.

    de Pontual, L., Kettaneh, D., Gordon, C. T., Oufadem, M., Boddaert, N., Lees, M., Balu, L., Lachassinne, E., Petros, A., Mollet, J., Wilson, L. C., Munnich, A., Brugière, L., Delattre, O., Vekemans, M., Etchevers, H., Lyonnet, S., Janoueix-Lerosey, I., & Amiel, J. (2011). Germline gain-of-function mutations of ALK disrupt central nervous system development. Human Mutation, 32(3), 272–276.

  31. 31.

    Mosse, Y. P., Lim, M. S., Voss, S. D., Wilner, K., Ruffner, K., Laliberte, J., et al. (2013). Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a children’s oncology group phase 1 consortium study. The Lancet Oncology, 14(6), 472–480.

  32. 32.

    Aubry, A., Galiacy, S., & Allouche, M. (2019). Targeting ALK in cancer: therapeutic potential of proapoptotic peptides. Cancers (Basel), 11(3).

  33. 33.

    Debruyne, D. N., Dries, R., Sengupta, S., Seruggia, D., Gao, Y., Sharma, B., Huang, H., Moreau, L., McLane, M., Day, D. S., Marco, E., Chen, T., Gray, N. S., Wong, K. K., Orkin, S. H., Yuan, G. C., Young, R. A., & George, R. E. (2019). BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells. Nature, 572(7771), 676–680.

  34. 34.

    De Mariano, M., Gallesio, R., Chierici, M., Furlanello, C., Conte, M., Garaventa, A., et al. (2015). Identification of GALNT14 as a novel neuroblastoma predisposition gene. Oncotarget, 6(28), 26335–26346.

  35. 35.

    Maris, J. M., Weiss, M. J., Mosse, Y., Hii, G., Guo, C., White, P. S., Hogarty, M. D., Mirensky, T., Brodeur, G. M., Rebbeck, T. R., Urbanek, M., & Shusterman, S. (2002). Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13. Cancer Research, 62(22), 6651–6658.

  36. 36.

    Perri, P., Longo, L., Cusano, R., McConville, C. M., Rees, S. A., Devoto, M., et al. (2002). Weak linkage at 4p16 to predisposition for human neuroblastoma. Oncogene, 21(54), 8356–8360.

  37. 37.

    Lo Cunsolo, C., Iolascon, A., Cavazzana, A., Cusano, R., Strigini, P., Mazzocco, K., Giordani, L., Massimo, L., de Bernardi, B., Conte, M., & Tonini, G. P. (1999). Neuroblastoma in two siblings supports the role of 1p36 deletion in tumor development. Cancer Genetics and Cytogenetics, 109(2), 126–130.

  38. 38.

    Tonini, G. P., Lo Cunsolo, C., Cusano, R., Iolascon, A., Dagnino, M., Conte, M., Milanaccio, C., de Bernardi, B., Mazzocco, K., & Scaruffi, P. (1997). Loss of heterozygosity for chromosome 1p in familial neuroblastoma. European Journal of Cancer, 33(12), 1953–1956.

  39. 39.

    Longo, L., Tonini, G. P., Ceccherini, I., & Perri, P. (2005). Oligogenic inheritance in neuroblastoma. Cancer Letters, 228(1–2), 65–69.

  40. 40.

    Kamihara, J., Bourdeaut, F., Foulkes, W. D., Molenaar, J. J., Mosse, Y. P., Nakagawara, A., et al. (2017). Retinoblastoma and neuroblastoma predisposition and surveillance. Clinical Cancer Research, 23(13), e98–e106.

  41. 41.

    Lasorsa, V. A., Formicola, D., Pignataro, P., Cimmino, F., Calabrese, F. M., Mora, J., et al. (2016). Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression. Oncotarget, 7(16), 21840–21852.

  42. 42.

    Esposito, M. R., Binatti, A., Pantile, M., Coppe, A., Mazzocco, K., Longo, L., Capasso, M., Lasorsa, V. A., Luksch, R., Bortoluzzi, S., & Tonini, G. P. (2018). Somatic mutations in specific and connected subpathways are associated with short neuroblastoma patients’ survival and indicate proteins targetable at onset of disease. International Journal of Cancer, 143(10), 2525–2536.

  43. 43.

    Pugh, T. J., Morozova, O., Attiyeh, E. F., Asgharzadeh, S., Wei, J. S., Auclair, D., Carter, S. L., Cibulskis, K., Hanna, M., Kiezun, A., Kim, J., Lawrence, M. S., Lichenstein, L., McKenna, A., Pedamallu, C. S., Ramos, A. H., Shefler, E., Sivachenko, A., Sougnez, C., Stewart, C., Ally, A., Birol, I., Chiu, R., Corbett, R. D., Hirst, M., Jackman, S. D., Kamoh, B., Khodabakshi, A. H., Krzywinski, M., Lo, A., Moore, R. A., Mungall, K. L., Qian, J., Tam, A., Thiessen, N., Zhao, Y., Cole, K. A., Diamond, M., Diskin, S. J., Mosse, Y. P., Wood, A. C., Ji, L., Sposto, R., Badgett, T., London, W. B., Moyer, Y., Gastier-Foster, J. M., Smith, M. A., Guidry Auvil, J. M., Gerhard, D. S., Hogarty, M. D., Jones, S. J., Lander, E. S., Gabriel, S. B., Getz, G., Seeger, R. C., Khan, J., Marra, M. A., Meyerson, M., & Maris, J. M. (2013). The genetic landscape of high-risk neuroblastoma. Nature Genetics, 45(3), 279–284.

  44. 44.

    Parsons, D. W., Roy, A., Yang, Y., Wang, T., Scollon, S., Bergstrom, K., et al. (2016). Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncology, 2(5), 616–624.

  45. 45.

    Diskin, S. J., Capasso, M., Diamond, M., Oldridge, D. A., Conkrite, K., Bosse, K. R., et al. (2014). Rare variants in TP53 and susceptibility to neuroblastoma. Journal of the National Cancer Institute, 106(4), dju047.

  46. 46.

    Origone, P., Defferrari, R., Mazzocco, K., Lo Cunsolo, C., De Bernardi, B., & Tonini, G. P. (2003). Homozygous inactivation of NF1 gene in a patient with familial NF1 and disseminated neuroblastoma. American Journal of Medical Genetics. Part A, 118A(4), 309–313.

  47. 47.

    Mutesa, L., Pierquin, G., Janin, N., Segers, K., Thomee, C., Provenzi, M., et al. (2008). Germline PTPN11 missense mutation in a case of Noonan syndrome associated with mediastinal and retroperitoneal neuroblastic tumors. Cancer Genetics and Cytogenetics, 182(1), 40–42.

  48. 48.

    Kratz, C. P., Rapisuwon, S., Reed, H., Hasle, H., & Rosenberg, P. S. (2011). Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 157C(2), 83–89.

  49. 49.

    Birch, J. M., Alston, R. D., McNally, R. J., Evans, D. G., Kelsey, A. M., Harris, M., et al. (2001). Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene, 20(34), 4621–4628.

  50. 50.

    Tatton-Brown, K., Murray, A., Hanks, S., Douglas, J., Armstrong, R., Banka, S., Bird, L. M., Clericuzio, C. L., Cormier-Daire, V., Cushing, T., Flinter, F., Jacquemont, M. L., Joss, S., Kinning, E., Lynch, S. A., Magee, A., McConnell, V., Medeira, A., Ozono, K., Patton, M., Rankin, J., Shears, D., Simon, M., Splitt, M., Strenger, V., Stuurman, K., Taylor, C., Titheradge, H., van Maldergem, L., Temple, I. K., Cole, T., Seal, S., Childhood Overgrowth Consortium, & Rahman, N. (2013). Weaver syndrome and EZH2 mutations: clarifying the clinical phenotype. American Journal of Medical Genetics. Part A, 161A(12), 2972–2980.

  51. 51.

    Schimke, R. N., Collins, D. L., & Stolle, C. A. (2010). Paraganglioma, neuroblastoma, and a SDHB mutation: resolution of a 30-year-old mystery. American Journal of Medical Genetics. Part A, 152A(6), 1531–1535.

  52. 52.

    Maas, S. M., Vansenne, F., Kadouch, D. J., Ibrahim, A., Bliek, J., Hopman, S., Mannens, M. M., Merks, J. H., Maher, E. R., & Hennekam, R. C. (2016). Phenotype, cancer risk, and surveillance in Beckwith-Wiedemann syndrome depending on molecular genetic subgroups. American Journal of Medical Genetics. Part A, 170(9), 2248–2260.

  53. 53.

    Ozcan, A., Acer, H., Ciraci, S., Gumus, H., Karakukcu, M., Patiroglu, T., et al. (2017). Neuroblastoma in a child with Wolf-Hirschhorn syndrome. Journal of Pediatric Hematology/Oncology, 39(4), e224–e226.

  54. 54.

    Maris, J. M., Mosse, Y. P., Bradfield, J. P., Hou, C., Monni, S., Scott, R. H., et al. (2008). Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. The New England Journal of Medicine, 358(24), 2585–2593.

  55. 55.

    Russell, M. R., Penikis, A., Oldridge, D. A., Alvarez-Dominguez, J. R., McDaniel, L., Diamond, M., Padovan, O., Raman, P., Li, Y., Wei, J. S., Zhang, S., Gnanchandran, J., Seeger, R., Asgharzadeh, S., Khan, J., Diskin, S. J., Maris, J. M., & Cole, K. A. (2015). CASC15-S is a tumor suppressor lncRNA at the 6p22 neuroblastoma susceptibility locus. Cancer Research, 75(15), 3155–3166.

  56. 56.

    Capasso, M., Diskin, S. J., Totaro, F., Longo, L., De Mariano, M., Russo, R., et al. (2013). Replication of GWAS-identified neuroblastoma risk loci strengthens the role of BARD1 and affirms the cumulative effect of genetic variations on disease susceptibility. Carcinogenesis, 34(3), 605–611.

  57. 57.

    Zhang, J., Zhuo, Z. J., Wang, J., He, J., Yang, L., Zhang, D., et al. (2017). CASC15 gene polymorphisms reduce neuroblastoma risk in Chinese children. Oncotarget, 8(53), 91343–91349.

  58. 58.

    Pandey, G. K., Mitra, S., Subhash, S., Hertwig, F., Kanduri, M., Mishra, K., Fransson, S., Ganeshram, A., Mondal, T., Bandaru, S., Ostensson, M., Akyürek, L. M., Abrahamsson, J., Pfeifer, S., Larsson, E., Shi, L., Peng, Z., Fischer, M., Martinsson, T., Hedborg, F., Kogner, P., & Kanduri, C. (2014). The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation. Cancer Cell, 26(5), 722–737.

  59. 59.

    Mondal, T., Juvvuna, P. K., Kirkeby, A., Mitra, S., Kosalai, S. T., Traxler, L., Hertwig, F., Wernig-Zorc, S., Miranda, C., Deland, L., Volland, R., Bartenhagen, C., Bartsch, D., Bandaru, S., Engesser, A., Subhash, S., Martinsson, T., Carén, H., Akyürek, L. M., Kurian, L., Kanduri, M., Huarte, M., Kogner, P., Fischer, M., & Kanduri, C. (2018). Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis. Cancer Cell, 33(3), 417–434 e417.

  60. 60.

    Capasso, M., Devoto, M., Hou, C., Asgharzadeh, S., Glessner, J. T., Attiyeh, E. F., Mosse, Y. P., Kim, C., Diskin, S. J., Cole, K. A., Bosse, K., Diamond, M., Laudenslager, M., Winter, C., Bradfield, J. P., Scott, R. H., Jagannathan, J., Garris, M., McConville, C., London, W. B., Seeger, R. C., Grant, S. F., Li, H., Rahman, N., Rappaport, E., Hakonarson, H., & Maris, J. M. (2009). Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nature Genetics, 41(6), 718–723.

  61. 61.

    Latorre, V., Diskin, S. J., Diamond, M. A., Zhang, H., Hakonarson, H., Maris, J. M., & Devoto, M. (2012). Replication of neuroblastoma SNP association at the BARD1 locus in African-Americans. Cancer Epidemiology, Biomarkers & Prevention, 21(4), 658–663.

  62. 62.

    Zhang, R., Zou, Y., Zhu, J., Zeng, X., Yang, T., Wang, F., He, J., & Xia, H. (2016). The association between GWAS-identified BARD1 gene SNPs and neuroblastoma susceptibility in a southern Chinese population. International Journal of Medical Sciences, 13(2), 133–138.

  63. 63.

    Cimmino, F., Avitabile, M., Diskin, S. J., Vaksman, Z., Pignataro, P., Formicola, D., Cardinale, A., Testori, A., Koster, J., de Torres, C., Devoto, M., Maris, J. M., Iolascon, A., & Capasso, M. (2018). Fine mapping of 2q35 high-risk neuroblastoma locus reveals independent functional risk variants and suggests full-length BARD1 as tumor-suppressor. International Journal of Cancer, 143(11), 2828–2837.

  64. 64.

    Oldridge, D. A., Truong, B., Russ, D., DuBois, S. G., Vaksman, Z., Mosse, Y. P., et al. (2019). Differences in genomic profiles and outcomes between thoracic and adrenal neuroblastoma. Journal of the National Cancer Institute.

  65. 65.

    Cimmino, F., Formicola, D., & Capasso, M. (2017). Dualistic role of BARD1 in cancer. Genes (Basel), 8(12).

  66. 66.

    Bosse, K. R., Diskin, S. J., Cole, K. A., Wood, A. C., Schnepp, R. W., Norris, G., Nguyen le, B., Jagannathan, J., Laquaglia, M., Winter, C., Diamond, M., Hou, C., Attiyeh, E. F., Mosse, Y. P., Pineros, V., Dizin, E., Zhang, Y., Asgharzadeh, S., Seeger, R. C., Capasso, M., Pawel, B. R., Devoto, M., Hakonarson, H., Rappaport, E. F., Irminger-Finger, I., & Maris, J. M. (2012). Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity. Cancer Research, 72(8), 2068–2078.

  67. 67.

    Wang, K., Diskin, S. J., Zhang, H., Attiyeh, E. F., Winter, C., Hou, C., Schnepp, R. W., Diamond, M., Bosse, K., Mayes, P. A., Glessner, J., Kim, C., Frackelton, E., Garris, M., Wang, Q., Glaberson, W., Chiavacci, R., Nguyen, L., Jagannathan, J., Saeki, N., Sasaki, H., Grant, S. F., Iolascon, A., Mosse, Y. P., Cole, K. A., Li, H., Devoto, M., McGrady, P., London, W. B., Capasso, M., Rahman, N., Hakonarson, H., & Maris, J. M. (2011). Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature, 469(7329), 216–220.

  68. 68.

    He, L., Zhu, J., Han, F., Tang, Y., Zhou, C., Dai, J., Wang, Y., Zhou, H., He, J., & Wu, H. (2018). LMO1 gene polymorphisms reduce neuroblastoma risk in eastern Chinese children: a three-center case-control study. Frontiers in Oncology, 8, 468.

  69. 69.

    Matthews, J. M., Lester, K., Joseph, S., & Curtis, D. J. (2013). LIM-domain-only proteins in cancer. Nature Reviews. Cancer, 13(2), 111–122.

  70. 70.

    Zhu, S., Zhang, X., Weichert-Leahey, N., Dong, Z., Zhang, C., Lopez, G., Tao, T., He, S., Wood, A. C., Oldridge, D., Ung, C. Y., van Ree, J., Khan, A., Salazar, B. M., Lummertz da Rocha, E., Zimmerman, M. W., Guo, F., Cao, H., Hou, X., Weroha, S. J., Perez-Atayde, A. R., Neuberg, D. S., Meves, A., McNiven, M., van Deursen, J., Li, H., Maris, J. M., & Look, A. T. (2017). LMO1 synergizes with MYCN to promote neuroblastoma initiation and metastasis. Cancer Cell, 32(3), 310–323 e315.

  71. 71.

    Oldridge, D. A., Wood, A. C., Weichert-Leahey, N., Crimmins, I., Sussman, R., Winter, C., McDaniel, L., Diamond, M., Hart, L. S., Zhu, S., Durbin, A. D., Abraham, B. J., Anders, L., Tian, L., Zhang, S., Wei, J. S., Khan, J., Bramlett, K., Rahman, N., Capasso, M., Iolascon, A., Gerhard, D. S., Guidry Auvil, J. M., Young, R. A., Hakonarson, H., Diskin, S. J., Look, A. T., & Maris, J. M. (2015). Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature, 528(7582), 418–421.

  72. 72.

    Diskin, S. J., Capasso, M., Schnepp, R. W., Cole, K. A., Attiyeh, E. F., Hou, C., Diamond, M., Carpenter, E. L., Winter, C., Lee, H., Jagannathan, J., Latorre, V., Iolascon, A., Hakonarson, H., Devoto, M., & Maris, J. M. (2012). Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nature Genetics, 44(10), 1126–1130.

  73. 73.

    He, J., Yang, T., Zhang, R., Zhu, J., Wang, F., Zou, Y., & Xia, H. (2016). Potentially functional polymorphisms in the LIN28B gene contribute to neuroblastoma susceptibility in Chinese children. Journal of Cellular and Molecular Medicine, 20(8), 1534–1541.

  74. 74.

    Powers, J. T., Tsanov, K. M., Pearson, D. S., Roels, F., Spina, C. S., Ebright, R., Seligson, M., de Soysa, Y., Cahan, P., Theißen, J., Tu, H. C., Han, A., Kurek, K. C., LaPier, G., Osborne, J. K., Ross, S. J., Cesana, M., Collins, J. J., Berthold, F., & Daley, G. Q. (2016). Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma. Nature, 535(7611), 246–251.

  75. 75.

    Schnepp, R. W., Khurana, P., Attiyeh, E. F., Raman, P., Chodosh, S. E., Oldridge, D. A., Gagliardi, M. E., Conkrite, K. L., Asgharzadeh, S., Seeger, R. C., Madison, B. B., Rustgi, A. K., Maris, J. M., & Diskin, S. J. (2015). A LIN28B-RAN-AURKA signaling network promotes neuroblastoma tumorigenesis. Cancer Cell, 28(5), 599–609.

  76. 76.

    Molenaar, J. J., Domingo-Fernandez, R., Ebus, M. E., Lindner, S., Koster, J., Drabek, K., et al. (2012). LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nature Genetics, 44(11), 1199–1206.

  77. 77.

    Corallo, D., Donadon, M., Pantile, M., Sidarovich, V., Cocchi, S., Ori, M., de Sarlo, M., Candiani, S., Frasson, C., Distel, M., Quattrone, A., Zanon, C., Basso, G., Tonini, G. P., & Aveic, S. (2019). LIN28B increases neural crest cell migration and leads to transformation of trunk sympathoadrenal precursors. Cell Death and Differentiation, 1–18.

  78. 78.

    Capasso, M., Calabrese, F. M., Iolascon, A., & Mellerup, E. (2014). Combinations of genetic data in a study of neuroblastoma risk genotypes. Cancer Genetics, 207(3), 94–97.

  79. 79.

    McDaniel, L. D., Conkrite, K. L., Chang, X., Capasso, M., Vaksman, Z., Oldridge, D. A., et al. (2017). Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma. PLoS Genetics, 13(5), e1006787.

  80. 80.

    Tang, J., Liu, W., Zhu, J., Zhang, J., Wang, F. H., Liang, J. H., Zeng, J. H., Wang, H., Xia, H., & He, J. (2018). RSRC1 and CPZ gene polymorphisms with neuroblastoma susceptibility in Chinese children. Gene, 662, 83–87.

  81. 81.

    Nguyen le, B., Diskin, S. J., Capasso, M., Wang, K., Diamond, M. A., Glessner, J., et al. (2011). Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility loci. PLoS Genetics, 7(3), e1002026.

  82. 82.

    Zhang, Z., Zou, Y., Zhu, J., Zhang, R., Yang, T., Wang, F., Xia, H., He, J., & Feng, Z. (2017). HSD17B12 gene rs11037575 C>T polymorphism confers neuroblastoma susceptibility in a southern Chinese population. Onco Targets Ther, 10, 1969–1975.

  83. 83.

    Gamazon, E. R., Pinto, N., Konkashbaev, A., Im, H. K., Diskin, S. J., London, W. B., Maris, J. M., Dolan, M. E., Cox, N. J., & Cohn, S. L. (2013). Trans-population analysis of genetic mechanisms of ethnic disparities in neuroblastoma survival. Journal of the National Cancer Institute, 105(4), 302–309.

  84. 84.

    Capasso, M., Diskin, S., Cimmino, F., Acierno, G., Totaro, F., Petrosino, G., Pezone, L., Diamond, M., McDaniel, L., Hakonarson, H., Iolascon, A., Devoto, M., & Maris, J. M. (2014). Common genetic variants in NEFL influence gene expression and neuroblastoma risk. Cancer Research, 74(23), 6913–6924.

  85. 85.

    Capasso, M., McDaniel, L. D., Cimmino, F., Cirino, A., Formicola, D., Russell, M. R., et al. (2017). The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma. Journal of Cellular and Molecular Medicine, 21(12), 3224–3230.

  86. 86.

    Chang, X., Zhao, Y., Hou, C., Glessner, J., McDaniel, L., Diamond, M. A., et al. (2017). Common variants in MMP20 at 11q22.2 predispose to 11q deletion and neuroblastoma risk. Nature Communications, 8(1), 569.

  87. 87.

    Hungate, E. A., Applebaum, M. A., Skol, A. D., Vaksman, Z., Diamond, M., McDaniel, L., Volchenboum, S. L., Stranger, B. E., Maris, J. M., Diskin, S. J., Onel, K., & Cohn, S. L. (2017). Evaluation of genetic predisposition for MYCN-amplified neuroblastoma. Journal of the National Cancer Institute, 109(10).

  88. 88.

    Testori, A., Lasorsa, V. A., Cimmino, F., Cantalupo, S., Cardinale, A., Avitabile, M., Limongelli, G., Russo, M. G., Diskin, S., Maris, J., Devoto, M., Keavney, B., Cordell, H. J., Iolascon, A., & Capasso, M. (2019). Exploring shared susceptibility between two neural crest cells originating conditions: neuroblastoma and congenital heart disease. Genes (Basel), 10(9).

  89. 89.

    Avitabile, M., Succoio, M., Testori, A., Cardinale, A., Vaksman, Z., Lasorsa, V. A., et al. (2019). Neural crest-derived tumor neuroblastoma and melanoma share 1p13.2 as susceptibility locus that shows a long-range interaction with the SLC16A1 gene. Carcinogenesis.

  90. 90.

    Egolf, L. E., Vaksman, Z., Lopez, G., Rokita, J. L., Modi, A., Basta, P. V., Hakonarson, H., Olshan, A. F., & Diskin, S. J. (2019). Germline 16p11.2 microdeletion predisposes to neuroblastoma. American Journal of Human Genetics, 105(3), 658–668.

  91. 91.

    Gambale, A., Russo, R., Andolfo, I., Quaglietta, L., De Rosa, G., Contestabile, V., et al. (2019). Germline mutations and new copy number variants among 40 pediatric cancer patients suspected for genetic predisposition. Clinical Genetics, 96(4), 359–365.

  92. 92.

    Tsubota, S., & Kadomatsu, K. (2018). Origin and initiation mechanisms of neuroblastoma. Cell and Tissue Research, 372(2), 211–221.

  93. 93.

    Johnsen, J. I., Dyberg, C., & Wickstrom, M. (2019). Neuroblastoma-a neural crest derived embryonal malignancy. Frontiers in Molecular Neuroscience, 12, 9.

  94. 94.

    Esposito, M. R., Aveic, S., Seydel, A., & Tonini, G. P. (2017). Neuroblastoma treatment in the post-genomic era. Journal of Biomedical Science, 24(1), 14.

  95. 95.

    Franke, F., Rudolph, B., Christiansen, H., Harbott, J., & Lampert, F. (1986). Tumour karyotype may be important in the prognosis of human neuroblastoma. Journal of Cancer Research and Clinical Oncology, 111(3), 266–272.

  96. 96.

    Schwab, M., Alitalo, K., Klempnauer, K. H., Varmus, H. E., Bishop, J. M., Gilbert, F., et al. (1983). Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature, 305(5931), 245–248.

  97. 97.

    Brodeur, G. M., Green, A. A., Hayes, F. A., Williams, K. J., Williams, D. L., & Tsiatis, A. A. (1981). Cytogenetic features of human neuroblastomas and cell lines. Cancer Research, 41(11 Pt 1), 4678–4686.

  98. 98.

    Brodeur, G. M., Seeger, R. C., Schwab, M., Varmus, H. E., & Bishop, J. M. (1984). Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science, 224(4653), 1121–1124.

  99. 99.

    Attiyeh, E. F., London, W. B., Mosse, Y. P., Wang, Q., Winter, C., Khazi, D., et al. (2005). Chromosome 1p and 11q deletions and outcome in neuroblastoma. The New England Journal of Medicine, 353(21), 2243–2253.

  100. 100.

    Thompson, P. M., Seifried, B. A., Kyemba, S. K., Jensen, S. J., Guo, C., Maris, J. M., et al. (2001). Loss of heterozygosity for chromosome 14q in neuroblastoma. Medical and Pediatric Oncology, 36(1), 28–31.<28::AID-MPO1008>3.0.CO;2-0.

  101. 101.

    Scaruffi, P., Coco, S., Cifuentes, F., Albino, D., Nair, M., Defferrari, R., Mazzocco, K., & Tonini, G. P. (2007). Identification and characterization of DNA imbalances in neuroblastoma by high-resolution oligonucleotide array comparative genomic hybridization. Cancer Genetics and Cytogenetics, 177(1), 20–29.

  102. 102.

    Schleiermacher, G., Mosseri, V., London, W. B., Maris, J. M., Brodeur, G. M., Attiyeh, E., Haber, M., Khan, J., Nakagawara, A., Speleman, F., Noguera, R., Tonini, G. P., Fischer, M., Ambros, I., Monclair, T., Matthay, K. K., Ambros, P., Cohn, S. L., & Pearson, A. D. (2012). Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project. British Journal of Cancer, 107(8), 1418–1422.

  103. 103.

    Stigliani, S., Coco, S., Moretti, S., Oberthuer, A., Fischer, M., Theissen, J., Gallo, F., Garavent, A., Berthold, F., Bonassi, S., Tonini, G. P., & Scaruffi, P. (2012). High genomic instability predicts survival in metastatic high-risk neuroblastoma. Neoplasia, 14(9), 823–832.

  104. 104.

    Fusco, P., Esposito, M. R., & Tonini, G. P. (2018). Chromosome instability in neuroblastoma. Oncology Letters, 16(6), 6887–6894.

  105. 105.

    Vanneste, E., Voet, T., Le Caignec, C., Ampe, M., Konings, P., Melotte, C., et al. (2009). Chromosome instability is common in human cleavage-stage embryos. Nature Medicine, 15(5), 577–583.

  106. 106.

    Coco, S., Theissen, J., Scaruffi, P., Stigliani, S., Moretti, S., Oberthuer, A., Valdora, F., Fischer, M., Gallo, F., Hero, B., Bonassi, S., Berthold, F., & Tonini, G. P. (2012). Age-dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma. International Journal of Cancer, 131(7), 1591–1600.

  107. 107.

    Tonini, G. P. (2017). Growth, progression and chromosome instability of neuroblastoma: a new scenario of tumorigenesis? BMC Cancer, 17(1), 20.

  108. 108.

    Ikeda, Y., Lister, J., Bouton, J. M., & Buyukpamukcu, M. (1981). Congenital neuroblastoma, neuroblastoma in situ, and the normal fetal development of the adrenal. Journal of Pediatric Surgery, 16(4 Suppl 1), 636–644.

  109. 109.

    Janoueix-Lerosey, I., Schleiermacher, G., Michels, E., Mosseri, V., Ribeiro, A., Lequin, D., Vermeulen, J., Couturier, J., Peuchmaur, M., Valent, A., Plantaz, D., Rubie, H., Valteau-Couanet, D., Thomas, C., Combaret, V., Rousseau, R., Eggert, A., Michon, J., Speleman, F., & Delattre, O. (2009). Overall genomic pattern is a predictor of outcome in neuroblastoma. Journal of Clinical Oncology, 27(7), 1026–1033.

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Tonini, G.P., Capasso, M. Genetic predisposition and chromosome instability in neuroblastoma. Cancer Metastasis Rev (2020).

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  • Neuroblastoma
  • Chromosome instability
  • Allelic variance
  • Mutation
  • SNP