Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Acquired genetic alterations in tumor cells dictate the development of high-risk neuroblastoma and clinical outcomes

Authors: Faizan H. Khan, Vijayabaskar Pandian, Satishkumar Ramraj, Mohan Natarajan, Sheeja Aravindan, Terence S. Herman, Natarajan Aravindan

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

Determining the driving factors and molecular flow-through that define the switch from favorable to aggressive high-risk disease is critical to the betterment of neuroblastoma cure.

Methods

In this study, we examined the cytogenetic and tumorigenic physiognomies of distinct population of metastatic site- derived aggressive cells (MSDACs) from high-risk tumors, and showed the influence of acquired genetic rearrangements on poor patient outcomes.

Results

Karyotyping in SH-SY5Y and MSDACs revealed trisomy of 1q, with additional non-random chromosomal rearrangements on 1q32, 8p23, 9q34, 15q24, 22q13 (additions), and 7q32 (deletion). Array CGH analysis of individual clones of MSDACs revealed genetic alterations in chromosomes 1, 7, 8, and 22, corresponding to a gain in the copy numbers of LOC100288142, CD1C, CFHR3, FOXP2, MDFIC, RALYL, CSMD3, SAMD12-AS1, and MAL2, and a loss in ADAM5, LOC400927, APOBEC3B, RPL3, MGAT3, SLC25A17, EP300, L3MBTL2, SERHL, POLDIP3, A4GALT, and TTLL1. QPCR analysis and immunoblotting showed a definite association between DNA-copy number changes and matching transcriptional/translational expression in clones of MSDACs. Further, MSDACs exert a stem-like phenotype. Under serum-free conditions, MSDACs demonstrated profound tumorosphere formation ex vivo. Moreover, MSDACs exhibited high tumorigenic capacity in vivo and prompted aggressive metastatic disease. Tissue microarray analysis coupled with automated IHC revealed significant association of RALYL to the tumor grade in a cohort of 25 neuroblastoma patients. Clinical outcome association analysis showed a strong correlation between the expression of CFHR3, CSMD3, MDFIC, FOXP2, RALYL, POLDIP3, SLC25A17, SERHL, MGAT3, TTLL1, or LOC400927 and overall and relapse-free survival in patients with neuroblastoma.

Conclusion

Together, these data highlight the ongoing acquired genetic rearrangements in undifferentiated tumor-forming neural crest cells, and suggest that these alterations could switch favorable neuroblastoma to high-risk aggressive disease, promoting poor clinical outcomes.
Appendix
Available only for authorised users
Literature
1.
Latimer E, Anderson G, Sebire NJ. Ultrastructural features of neuroblastic tumours in relation to morphological, and molecular findings; a retrospective review study. BMC clinical pathology. 2014;14:13.CrossRefPubMedPubMedCentral
2.
Weinstein JL, Katzenstein HM, Cohn SL. Advances in the diagnosis and treatment of neuroblastoma. The oncologist. 2003;8(3):278–92.CrossRefPubMed
3.
Chen CY, Chiou SH, Huang CY, Jan CI, Lin SC, Tsai ML, et al. Distinct population of highly malignant cells in a head and neck squamous cell carcinoma cell line established by xenograft model. J Biomed Sci. 2009;16:100.CrossRefPubMedPubMedCentral
4.
Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med. 1999;341(16):1165–73.CrossRefPubMed
5.
George RE, Li S, Medeiros-Nancarrow C, Neuberg D, Marcus K, Shamberger RC, et al. High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol. 2006;24(18):2891–6.CrossRefPubMed
6.
Garaventa A, Parodi S, De Bernardi B, Dau D, Manzitti C, Conte M, et al. Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry. Eur J Cancer. 2009;45(16):2835–42.CrossRefPubMed
7.
London WB, Castel V, Monclair T, Ambros PF, Pearson AD, Cohn SL, et al. Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol. 2011;29(24):3286–92.CrossRefPubMedPubMedCentral
8.
9.
Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481(7382):506–10.CrossRefPubMedPubMedCentral
10.
Ambros PF, Ambros IM, Brodeur GM, Haber M, Khan J, Nakagawara A, et al. International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer. 2009;100(9):1471–82.CrossRefPubMedPubMedCentral
11.
George RE, Attiyeh EF, Li S, Moreau LA, Neuberg D, Li C, et al. Genome-wide analysis of neuroblastomas using high-density single nucleotide polymorphism arrays. PLoS One. 2007;2(2), e255.CrossRefPubMedPubMedCentral
12.
Schleiermacher G, Janoueix-Lerosey I, Ribeiro A, Klijanienko J, Couturier J, Pierron G, et al. Accumulation of segmental alterations determines progression in neuroblastoma. J Clin Oncol. 2010;28(19):3122–30.CrossRefPubMed
13.
Schleiermacher G, Michon J, Ribeiro A, Pierron G, Mosseri V, Rubie H, et al. Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study). Br J Cancer. 2011;105(12):1940–8.CrossRefPubMedPubMedCentral
14.
Stallings RL. Origin and functional significance of large-scale chromosomal imbalances in neuroblastoma. Cytogenet Genome Res. 2007;118(2–4):110–5.CrossRefPubMed
15.
Ross RA, Spengler BA, Biedler JL. Coordinate morphological and biochemical interconversion of human neuroblastoma cells. J Natl Cancer Inst. 1983;71(4):741–7.PubMed
16.
Spengler BA, Biedler JL, Ross RA. A corrected karyotype for the SH-SY5Y human neuroblastoma cell line. Cancer Genet Cytogenet. 2002;138(2):177–8.CrossRefPubMed
17.
Van Roy N, Van Limbergen H, Vandesompele J, Van Gele M, Poppe B, Salwen H, et al. Combined M-FISH and CGH analysis allows comprehensive description of genetic alterations in neuroblastoma cell lines. Genes Chromosomes Cancer. 2001;32(2):126–35.CrossRefPubMed
18.
Do JH, Kim IS, Park TK, Choi DK. Genome-wide examination of chromosomal aberrations in neuroblastoma SH-SY5Y cells by array-based comparative genomic hybridization. Mol Cells. 2007;24(1):105–12.PubMed
19.
Kryh H, Caren H, Erichsen J, Sjoberg RM, Abrahamsson J, Kogner P, et al. Comprehensive SNP array study of frequently used neuroblastoma cell lines; copy neutral loss of heterozygosity is common in the cell lines but uncommon in primary tumors. BMC genomics. 2011;12:443.CrossRefPubMedPubMedCentral
20.
Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003;3(3):203–16.CrossRefPubMed
21.
Spitz R, Oberthuer A, Zapatka M, Brors B, Hero B, Ernestus K, et al. Oligonucleotide array-based comparative genomic hybridization (aCGH) of 90 neuroblastomas reveals aberration patterns closely associated with relapse pattern and outcome. Genes Chromosomes Cancer. 2006;45(12):1130–42.CrossRefPubMed
22.
Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;27(2):289–97.CrossRefPubMedPubMedCentral
23.
Joshua BZ, Sachs O, Shelef I, Vardy-Sion N, Novack L, Vaiman M, et al. Comparison of clinical data, CT, and bone histopathology in unilateral chronic maxillary sinusitis. Otolaryngol Head Neck Surg. 2013;148(1):145–50.CrossRefPubMed
24.
Santana VM, Furman WL, McGregor LM, Billups CA. Disease control intervals in high-risk neuroblastoma. Cancer. 2008;112(12):2796–801.CrossRefPubMed
25.
Simon T, Berthold F, Borkhardt A, Kremens B, De Carolis B, Hero B. Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: results of German trials. Pediatric blood & cancer. 2011;56(4):578–83.CrossRef
26.
Veeraraghavan J, Natarajan M, Aravindan S, Herman TS, Aravindan N. Radiation-triggered tumor necrosis factor (TNF) alpha-NFkappaB cross-signaling favors survival advantage in human neuroblastoma cells. J Biol Chem. 2011;286(24):21588–600.CrossRefPubMedPubMedCentral
27.
Khan FH, Pandian V, Ramraj S, Aravindan S, Herman TS and Aravindan N. Reorganization of metastamiRs in the evolution of metastatic aggressive neuroblastoma cells. BMC Genomics. 2015;16:501 doi:10.​1186/​s12864-015-1642-x.
28.
Pandian V, Ramraj S, Khan FH, Azim T and Aravindan N. Metastatic neuroblastoma cancer stem cells exhibit flexible plasticity and adaptive stemness signaling. Stem Cell Research & Therapy. 2015;6(1):2. doi: 10.​1186/​s13287-015-0002-8.
29.
Khan FH, Ganesan P, Kumar S. Y Chromosome microdeletion and altered sperm quality in human males with high concentration of seminal hexachlorocyclohexane (HCH). Chemosphere. 2010;80(9):972–7.CrossRefPubMed
30.
Aravindan N, Madhusoodhanan R, Ahmad S, Johnson D, Herman TS. Curcumin inhibits NFkappaB mediated radioprotection and modulate apoptosis related genes in human neuroblastoma cells. Cancer Biol Ther. 2008;7(4):569–76.CrossRefPubMed
31.
Aravindan S, Natarajan M, Awasthi V, Herman TS, Aravindan N. Novel synthetic monoketone transmute radiation-triggered NFkappaB-dependent TNFalpha cross-signaling feedback maintained NFkappaB and favors neuroblastoma regression. PLoS One. 2013;8(8), e72464.CrossRefPubMedPubMedCentral
32.
Kovalevich J, Langford D. Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol Biol. 2013;1078:9–21.CrossRefPubMed
33.
34.
Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, et al. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature. 1983;305(5937):779–84.CrossRefPubMed
35.
Land H, Parada LF, Weinberg RA. Cellular oncogenes and multistep carcinogenesis. Science. 1983;222(4625):771–8.CrossRefPubMed
36.
Charafe-Jauffret E, Monville F, Ginestier C, Dontu G, Birnbaum D, Wicha MS. Cancer stem cells in breast: current opinion and future challenges. Pathobiology. 2008;75(2):75–84.CrossRefPubMedPubMedCentral
37.
Nicolson GL. Tumor cell instability, diversification, and progression to the metastatic phenotype: from oncogene to oncofetal expression. Cancer Res. 1987;47(6):1473–87.PubMed
38.
Kerbel RS, Viloria-Petit A, Okada F, Rak J. Establishing a link between oncogenes and tumor angiogenesis. Mol Med. 1998;4(5):286–95.PubMedPubMedCentral
39.
Sandberg AA, Meloni-Ehrig AM. Cytogenetics and genetics of human cancer: methods and accomplishments. Cancer Genet Cytogenet. 2010;203(2):102–26.CrossRefPubMed
40.
Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin. 2013;34(6):732–40.CrossRefPubMedPubMedCentral
41.
Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 2009;69(4):1302–13.CrossRefPubMedPubMedCentral
42.
Fidler IJ. Selection of successive tumour lines for metastasis. Nat New Biol. 1973;242(118):148–9.CrossRefPubMed
43.
Fidler IJ. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res. 1990;50(19):6130–8.PubMed
Metadata
Title
Acquired genetic alterations in tumor cells dictate the development of high-risk neuroblastoma and clinical outcomes
Authors
Faizan H. Khan
Vijayabaskar Pandian
Satishkumar Ramraj
Mohan Natarajan
Sheeja Aravindan
Terence S. Herman
Natarajan Aravindan
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1463-y

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

AXL is a potential therapeutic target in dedifferentiated and pleomorphic liposarcomas

Research article

COP1, the negative regulator of ETV1, influences prognosis in triple-negative breast cancer

Research article

Intra-tumor heterogeneity in TP53 null High Grade Serous Ovarian Carcinoma progression

Research article

Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo

Research article

Comparison of first-line chemotherapy based on irinotecan or other drugs to treat non-small cell lung cancer in stage IIIB/IV: a systematic review and meta-analysis

Research article

Gamma knife radiosurgery for elderly patients with brain metastases: evaluation of scoring systems that predict survival
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits