Identification of recurrent 3q13.31 chromosomal rearrangement indicates <em>LSAMP</em> as a tumor suppressor gene in neuroblastoma

Martinez-Monleon,Angela; Gaarder,Jennie; Djos,Anna; Kogner,Per; Fransson,Susanne

doi:10.3892/ijo.2023.5475

February-2023 Volume 62 Issue 2

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February-2023 Volume 62 Issue 2

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Identification of recurrent 3q13.31 chromosomal rearrangement indicates LSAMP as a tumor suppressor gene in neuroblastoma

Authors:
- Angela Martinez-Monleon
- Jennie Gaarder
- Anna Djos
- Per Kogner
- Susanne Fransson
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Affiliations: Department of Laboratory Medicine, Sahlgrenska Academy at University of Gothenburg, SE‑405 30 Gothenburg, Sweden, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, SE‑171 77 Stockholm, Sweden

Copyright: © Martinez-Monleon et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 27
|
Published online on: January 3, 2023

https://doi.org/10.3892/ijo.2023.5475
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Abstract

Neuroblastoma (NB) is a childhood malignancy of the sympathetic nervous system. NB is mainly driven by copy number alterations, such as MYCN amplification, large deletions of chromosome arm 11q and gain of chromosome arm 17q, which are all markers of high‑risk disease. Genes targeted by recurrent, smaller, focal alterations include CDKN2A/B, TERT, PTPRD and ATRX. Our previous study on relapsed NB detected recurrent structural alterations centered at limbic system‑associated membrane protein (LSAMP; HUGO Gene Nomenclature Committee: 6705; chromosomal location 3q13.31), which is a gene frequently reported to be deleted or downregulated in other types of cancer. Notably, in cancer, LSAMP has been shown to have tumor‑suppressing functions. The present study performed an expanded investigation using whole genome sequencing of tumors from 35 patients, mainly with high‑risk NB. Focal duplications or deletions targeting LSAMP were detected in six cases (17%), whereas single nucleotide polymorphism‑microarray analysis of 16 NB cell lines detected segmental alterations at 3q13.31 in seven out of the 16 NB cell lines (44%). Furthermore, low expression of LSAMP in NB tumors was significantly associated with poor overall and event‑free survival. In vitro, knockdown of LSAMP in NB cell lines increased cell proliferation, whereas overexpression decreased proliferation and viability. These findings supported a tumor suppressor role for LSAMP in NB. However, the higher incidence of LSAMP aberrations in cell lines and in relapsed NB tumors suggested that these alterations were a late event predominantly in advanced NB with a poor prognosis, indicating a role of LSAMP in tumor progression rather than in tumor initiation. In conclusion, the present study demonstrated recurrent genomic aberrations of chromosomal region 3q13.31 that targeted the LSAMP gene, which encodes a membrane protein involved in cell adhesion, central nervous system development and neurite outgrowth. The frequent aberrations affecting LSAMP, together with functional evidence, suggested an anti‑proliferative role of LSAMP in NB.

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1	Diller GP and Baumgartner H: Sudden cardiac death during exercise in patients with congenital heart disease: The exercise paradox and the challenge of appropriate counselling. Eur Heart J. 37:627–629. 2016. View Article : Google Scholar
2	Stiller CA and Parkin DM: International variations in the incidence of neuroblastoma. Int J Cancer. 52:538–543. 1992. View Article : Google Scholar : PubMed/NCBI
3	Park JR, Eggert A and Caron H: Neuroblastoma: Biology, prognosis, and treatment. Hematol Oncol Clin North Am. 24:65–86. 2010. View Article : Google Scholar : PubMed/NCBI
4	London WB, Castleberry RP, Matthay KK, Look AT, Seeger RC, Shimada H, Thorner P, Brodeur G, Maris JM, Reynolds CP and Cohn SL: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the children's oncology group. J Clin Oncol. 23:6459–6465. 2005. View Article : Google Scholar : PubMed/NCBI
5	Maris JM, Hogarty MD, Bagatell R and Cohn SL: Neuroblastoma. Lancet. 369:2106–2120. 2007. View Article : Google Scholar : PubMed/NCBI
6	Janoueix-Lerosey I, Schleiermacher G, Michels E, Mosseri V, Ribeiro A, Lequin D, Vermeulen J, Couturier J, Peuchmaur M, Valent A, et al: Overall genomic pattern is a predictor of outcome in neuroblastoma. J Clin Oncol. 27:1026–1033. 2009. View Article : Google Scholar : PubMed/NCBI
7	Caren H, Kryh H, Nethander M, Sjöberg RM, Träger C, Nilsson S, Abrahamsson J, Kogner P and Martinsson T: High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. Proc Natl Acad Sci USA. 107:4323–4328. 2010. View Article : Google Scholar : PubMed/NCBI
8	Guimier A, Ferrand S, Pierron G, Couturier J, Janoueix-Lerosey I, Combaret V, Mosseri V, Thebaud E, Gambart M, Plantaz D, et al: Clinical characteristics and outcome of patients with neuroblastoma presenting genomic amplification of loci other than MYCN. PLoS One. 9:e1019902014. View Article : Google Scholar : PubMed/NCBI
9	Martinez-Monleon A, Oberg HK, Gaarder J, Berbegall AP, Javanmardi N, Djos A, Ussowicz M, Taschner-Mandl S, Ambros IM, Øra I, et al: Amplification of CDK4 and MDM2: A detailed study of a high-risk neuroblastoma subgroup. Sci Rep. 12:124202022. View Article : Google Scholar : PubMed/NCBI
10	Molenaar JJ, Koster J, Ebus ME, van Sluis P, Westerhout EM, de Preter K, Gisselsson D, Øra I, Speleman F, Caron HN and Versteeg R: Copy number defects of G1-cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis. Genes Chromosomes Cancer. 51:10–19. 2012. View Article : Google Scholar
11	Ackermann S, Cartolano M, Hero B, Welte A, Kahlert Y, Roderwieser A, Bartenhagen C, Walter E, Gecht J, Kerschke L, et al: A mechanistic classification of clinical phenotypes in neuroblastoma. Science. 362:1165–1170. 2018. View Article : Google Scholar : PubMed/NCBI
12	Fransson S, Martinez-Monleon A, Johansson M, Sjöberg RM, Björklund C, Ljungman G, Ek T, Kogner P and Martinsson T: Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance. Sci Rep. 10:224322020. View Article : Google Scholar
13	Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, Hamdi M, van Nes J, Westerman BA, van Arkel J, et al: Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature. 483:589–593. 2012. View Article : Google Scholar : PubMed/NCBI
14	Chen QR, Bilke S, Wei JS, Whiteford CC, Cenacchi N, Krasnoselsky AL, Greer BT, Son CG, Westermann F, Berthold F, et al: cDNA array-CGH profiling identifies genomic alterations specific to stage and MYCN-amplification in neuroblastoma. BMC Genomics. 5:702004. View Article : Google Scholar : PubMed/NCBI
15	Vandesompele J, Speleman F, Van Roy N, Laureys G, Brinskchmidt C, Christiansen H, Lampert F, Lastowska M, Bown N, Pearson A, et al: Multicentre analysis of patterns of DNA gains and losses in 204 neuroblastoma tumors: How many genetic subgroups are there? Med Pediatr Oncol. 36:5–10. 2001. View Article : Google Scholar : PubMed/NCBI
16	Fransson S, Ostensson M, Djos A, Javanmardi N, Kogner P and Martinsson T: Estimation of copy number aberrations: Comparison of exome sequencing data with SNP microarrays identifies homozygous deletions of 19q13.2 and CIC in neuroblastoma. Int J Oncol. 48:1103–1116. 2016. View Article : Google Scholar : PubMed/NCBI
17	Lopez G, Conkrite KL, Doepner M, Rathi KS, Modi A, Vaksman Z, Farra LM, Hyson E, Noureddine M, Wei JS, et al: Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma. Genome Res. 30:1228–1242. 2020. View Article : Google Scholar : PubMed/NCBI
18	Kubick N, Brosamle D and Mickael ME: Molecular evolution and functional divergence of the IgLON family. Evol Bioinform Online. 14:11769343187750812018. View Article : Google Scholar : PubMed/NCBI
19	Kimura Y, Katoh A, Kaneko T, Takahama K and Tanaka H: Two members of the IgLON family are expressed in a restricted region of the developing chick brain and neural crest. Dev Growth Differ. 43:257–263. 2001. View Article : Google Scholar : PubMed/NCBI
20	Pischedda F and Piccoli G: The IgLON family member Negr1 promotes neuronal arborization acting as soluble factor via FGFR2. Front Mol Neurosci. 8:892015.
21	Yamada M, Hashimoto T, Hayashi N, Higuchi M, Murakami A, Nakashima T, Maekawa S and Miyata S: Synaptic adhesion molecule OBCAM; synaptogenesis and dynamic internalization. Brain Res. 1165:5–14. 2007. View Article : Google Scholar : PubMed/NCBI
22	Hashimoto T, Maekawa S and Miyata S: IgLON cell adhesion molecules regulate synaptogenesis in hippocampal neurons. Cell Biochem Funct. 27:496–498. 2009. View Article : Google Scholar : PubMed/NCBI
23	Minhas HM, Pescosolido MF, Schwede M, Piasecka J, Gaitanis J, Tantravahi U and Morrow EM: An unbalanced translocation involving loss of 10q26.2 and gain of 11q25 in a pedigree with autism spectrum disorder and cerebellar juvenile pilocytic astrocytoma. Am J Med Genet A. 161A:787–791. 2013. View Article : Google Scholar : PubMed/NCBI
24	Karis K, Eskla KL, Kaare M, Täht K, Tuusov J, Visnapuu T, Innos J, Jayaram M, Timmusk T, Weickert CS, et al: Altered expression profile of IgLON family of neural cell adhesion molecules in the dorsolateral prefrontal cortex of schizophrenic patients. Front Mol Neurosci. 11:82018. View Article : Google Scholar : PubMed/NCBI
25	Singh K, Jayaram M, Kaare M, Leidmaa E, Jagomäe T, Heinla I, Hickey MA, Kaasik A, Schäfer MK, Innos J, et al: Neural cell adhesion molecule Negr1 deficiency in mouse results in structural brain endophenotypes and behavioral deviations related to psychiatric disorders. Sci Rep. 9:54572019. View Article : Google Scholar : PubMed/NCBI
26	Ntougkos E, Rush R, Scott D, Frankenberg T, Gabra H, Smyth JF and Sellar GC: The IgLON family in epithelial ovarian cancer: Expression profiles and clinicopathologic correlates. Clin Cancer Res. 11:5764–5768. 2005. View Article : Google Scholar : PubMed/NCBI
27	Xing X, Cai W, Ma S, Wang Y, Shi H, Li M, Jiao J, Yang Y, Liu L, Zhang X and Chen M: Down-regulated expression of OPCML predicts an unfavorable prognosis and promotes disease progression in human gastric cancer. BMC Cancer. 17:2682017. View Article : Google Scholar : PubMed/NCBI
28	Zhang N, Xu J, Wang Y, Heng X, Yang L and Xing X: Loss of opioid binding protein/cell adhesion molecule-like gene expression in gastric cancer. Oncol Lett. 15:9973–9977. 2018.PubMed/NCBI
29	Tomolonis JA, Agarwal S and Shohet JM: Neuroblastoma pathogenesis: Deregulation of embryonic neural crest development. Cell Tissue Res. 372:245–262. 2018. View Article : Google Scholar :
30	Zhukareva V, Chernevskaya N, Pimenta A, Nowycky M and Levitt P: Limbic system-associated membrane protein (LAMP) induces neurite outgrowth and intracellular Ca2+ increase in primary fetal neurons. Mol Cell Neurosci. 10:43–55. 1997. View Article : Google Scholar : PubMed/NCBI
31	Sanz RL, Ferraro GB, Girouard MP and Fournier AE: Ectodomain shedding of limbic system-associated membrane protein (LSAMP) by ADAM metallopeptidases promotes neurite outgrowth in DRG neurons. Sci Rep. 7:79612017. View Article : Google Scholar : PubMed/NCBI
32	Koido K, Traks T, Balotsev R, Eller T, Must A, Koks S, Maron E, Tõru I, Shlik J, Vasar V and Vasar E: Associations between LSAMP gene polymorphisms and major depressive disorder and panic disorder. Transl Psychiatry. 2:e1522012. View Article : Google Scholar : PubMed/NCBI
33	Yen CC, Chen WM, Chen TH, York-Kwan WC, Chih-Hsueh PC, Chiou HJ, Hung GY, Wu HTH, Wei CJ, Shiau CY, et al: Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma. Int J Oncol. 35:775–788. 2009.PubMed/NCBI
34	Kresse SH, Ohnstad HO, Paulsen EB, Bjerkehagen B, Szuhai K, Serra M, Schaefer KL, Myklebost O and Meza-Zepeda LA: LSAMP, a novel candidate tumor suppressor gene in human osteosarcomas, identified by array comparative genomic hybridization. Genes Chromosomes Cancer. 48:679–693. 2009. View Article : Google Scholar : PubMed/NCBI
35	Pasic I, Shlien A, Durbin AD, Stavropoulos DJ, Baskin B, Ray PN, Novokmet A and Malkin D: Recurrent focal copy-number changes and loss of heterozygosity implicate two noncoding RNAs and one tumor suppressor gene at chromosome 3q13.31 in osteosarcoma. Cancer Res. 70:160–171. 2010. View Article : Google Scholar : PubMed/NCBI
36	Baroy T, Kresse SH, Skarn M, Stabell M, Castro R, Lauvrak S, Llombart-Bosch A, Myklebost O and Meza-Zepeda LA: Reexpression of LSAMP inhibits tumor growth in a preclinical osteosarcoma model. Mol Cancer. 13:932014. View Article : Google Scholar : PubMed/NCBI
37	Smida J, Xu H, Zhang Y, Baumhoer D, Ribi S, Kovac M, von Luettichau I, Bielack S, O'Leary VB, Leib-Mösch C, et al: Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma. Int J Cancer. 141:816–828. 2017. View Article : Google Scholar : PubMed/NCBI
38	Zhang L, Yuan Y, Lu KH and Zhang L: Identification of recurrent focal copy number variations and their putative targeted driver genes in ovarian cancer. BMC Bioinformatics. 17:2222016. View Article : Google Scholar : PubMed/NCBI
39	Chen J, Lui WO, Vos MD, Clark GJ, Takahashi M, Schoumans J, Khoo SK, Petillo D, Lavery T, Sugimura J, et al: The t(1;3) breakpoint-spanning genes LSAMP and NORE1 are involved in clear cell renal cell carcinomas. Cancer Cell. 4:405–413. 2003. View Article : Google Scholar : PubMed/NCBI
40	Petrovics G, Li H, Stumpel T, Tan SH, Young D, Katta S, Li Q, Ying K, Klocke B, Ravindranath L, et al: A novel genomic alteration of LSAMP associates with aggressive prostate cancer in African American men. EBioMedicine. 2:1957–1964. 2015. View Article : Google Scholar
41	Huang SP, Lin VC, Lee YC, Yu CC, Huang CY, Chang TY, Lee HZ, Juang SH, Lu TL and Bao BY: Genetic variants in nuclear factor-kappa B binding sites are associated with clinical outcomes in prostate cancer patients. Eur J Cancer. 49:3729–3737. 2013. View Article : Google Scholar : PubMed/NCBI
42	Nobusawa S, Hirato J, Kurihara H, Ogawa A, Okura N, Nagaishi M, Ikota H, Yokoo H and Nakazato Y: Intratumoral heterogeneity of genomic imbalance in a case of epithelioid glioblastoma with BRAF V600E mutation. Brain Pathol. 24:239–246. 2014. View Article : Google Scholar
43	Yoon J, Cho EH, Yun JW, Kim HY, Jang JH, Kim HJ and Kim SH: LSAMP rearrangement in acute myeloid leukemia with a jumping translocation involving 3q13.31. Ann Lab Med. 41:342–345. 2021. View Article : Google Scholar :
44	Chang CY, Wu KL, Chang YY, Liu YW, Huang YC, Jian SF, Lin YS, Tsai PH, Hung JY, Tsai YM and Hsu YL: The downregulation of LSAMP expression promotes lung cancer progression and is associated with poor survival prognosis. J Pers Med. 11:5782021. View Article : Google Scholar : PubMed/NCBI
45	Roller E, Ivakhno S, Lee S, Royce T and Tanner S: Canvas: Versatile and scalable detection of copy number variants. Bioinformatics. 32:2375–2377. 2016. View Article : Google Scholar : PubMed/NCBI
46	Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Källberg M, Cox AJ, Kruglyak S and Saunders CT: Manta: Rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 32:1220–1222. 2016. View Article : Google Scholar
47	Thorvaldsdottir H, Robinson JT and Mesirov JP: Integrative genomics viewer (IGV): High-performance genomics data visualization and exploration. Brief Bioinform. 14:178–192. 2013. View Article : Google Scholar :
48	Umapathy G, Guan J, Gustafsson DE, Javanmardi N, Cervantes-Madrid D, Djos A, Martinsson T, Palmer RH and Hallberg B: MEK inhibitor trametinib does not prevent the growth of anaplastic lymphoma kinase (ALK)-addicted neuroblastomas. Sci Signal. 10:eaam75502017. View Article : Google Scholar : PubMed/NCBI
49	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
50	Sellar GC, Watt KP, Rabiasz GJ, Stronach EA, Li L, Miller EP, Massie CE, Miller J, Contreras-Moreira B, Scott D, et al: OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer. Nat Genet. 34:337–343. 2003. View Article : Google Scholar : PubMed/NCBI
51	Reed JE, Dunn JR, du Plessis DG, Shaw EJ, Reeves P, Gee AL, Warnke PC, Sellar GC, Moss DJ and Walker C: Expression of cellular adhesion molecule 'OPCML' is down-regulated in gliomas and other brain tumours. Neuropathol Appl Neurobiol. 33:77–85. 2007. View Article : Google Scholar : PubMed/NCBI
52	Cui Y, Ying Y, van Hasselt A, Ng KM, Yu J, Zhang Q, Jin J, Liu D, Rhim JS, Rha SY, et al: OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation. PLoS One. 3:e29902008. View Article : Google Scholar : PubMed/NCBI
53	Kim H, Hwang JS, Lee B, Hong J and Lee S: Newly identified cancer-associated role of human neuronal growth regulator 1 (NEGR1). J Cancer. 5:598–608. 2014. View Article : Google Scholar : PubMed/NCBI
54	Abbasi MR, Rifatbegovic F, Brunner C, Mann G, Ziegler A, Pötschger U, Crazzolara R, Ussowicz M, Benesch M, Ebetsberger-Dachs G, et al: Impact of disseminated neuroblastoma cells on the identification of the relapse-seeding clone. Clin Cancer Res. 23:4224–4232. 2017. View Article : Google Scholar : PubMed/NCBI
55	Caron H: Allelic loss of chromosome 1 and additional chromosome 17 material are both unfavourable prognostic markers in neuroblastoma. Med Pediatr Oncol. 24:215–221. 1995. View Article : Google Scholar : PubMed/NCBI
56	Venkannagari H, Kasper JM, Misra A, Rush SA, Fan S, Lee H, Sun H, Seshadrinathan S, Machius M, Hommel JD and Rudenko G: Highly conserved molecular features in IgLONs contrast their distinct structural and biological outcomes. J Mol Biol. 432:5287–5303. 2020. View Article : Google Scholar : PubMed/NCBI
57	Reed J, McNamee C, Rackstraw S, Jenkins J and Moss D: Diglons are heterodimeric proteins composed of IgLON subunits, and Diglon-CO inhibits neurite outgrowth from cerebellar granule cells. J Cell Sci. 117:3961–3973. 2004. View Article : Google Scholar : PubMed/NCBI
58	Szczurkowska J, Pischedda F, Pinto B, Managò F, Haas CA, Summa M, Bertorelli R, Papaleo F, Schäfer MK, Piccoli G and Cancedda L: NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice. Brain. 141:2772–2794. 2018.PubMed/NCBI