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
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2009

Open Access 01-12-2009 | Research article

c.1810C>T Polymorphism of NTRK1Gene is associated with reduced Survival in Neuroblastoma Patients

Authors: Beata S Lipska, Elżbieta Drożynska, Paola Scaruffi, Gian Paolo Tonini, Ewa Iżycka-Świeszewska, Szymon Ziętkiewicz, Anna Balcerska, Danuta Perek, Alicja Chybicka, Wojciech Biernat, Janusz Limon

Published in: BMC Cancer | Issue 1/2009

Login to get access

Abstract

Background

TrkA (encoded by NTRK1 gene), the high-affinity tyrosine kinase receptor for neurotrophins, is involved in neural crest cell differentiation. Its expression has been reported to be associated with a favourable prognosis in neuroblastoma. Therefore, the entire coding sequence of NTRK1 gene has been analysed in order to identify mutations and/or polymorphisms which may alter TrkA receptor expression.

Methods

DNA was extracted from neuroblastomas of 55 Polish and 114 Italian patients and from peripheral blood leukocytes of 158 healthy controls. Denaturing High-Performance Liquid Chromatography (DHPLC) and Single-Strand Conformation Polymorphism (SSCP) analysis were used to screen for sequence variants. Genetic changes were confirmed by direct sequencing and correlated with biological and clinical data.

Results

Three previously reported and nine new single nucleotide polymorphisms were detected. c.1810C>T polymorphism present in 8.7% of cases was found to be an independent marker of disease recurrence (OR = 13.3; p = 0.009) associated with lower survival rates (HR = 4.45 p = 0.041). c.1810C>T polymorphism's unfavourable prognostic value was most significant in patients under 18 months of age with no MYCN amplification (HR = 26; p = 0.008). In-silico analysis of the c.1810C>T polymorphism suggests that the substitution of the corresponding amino acid residue within the conservative region of the tyrosine kinase domain might theoretically interfere with the functioning of the TrkA protein.

Conclusions

NTRK1 c.1810C>T polymorphism appears to be a new independent prognostic factor of poor outcome in neuroblastoma, especially in children under 18 months of age with no MYCN amplification.
Appendix
Available only for authorised users
Literature
1.
Isaacs H: Fetal and neonatal neuroblastoma. Retrospective review of 271 cases. Fetal Pediatr Pathol. 2007, 26: 177-84. 10.1080/15513810701696890.CrossRefPubMed
2.
Maris JM, Hogarty MD, Bagatell R, Cohn SL: Neuroblastoma. Lancet. 2007, 369: 2106-20. 10.1016/S0140-6736(07)60983-0.CrossRefPubMed
3.
Tanaka T, Sugimoto T, Sawada T: Prognostic discrimination among neuroblastomas according to Ha-ras/TrkA gene expression. Cancer. 1998, 83: 1626-33. 10.1002/(SICI)1097-0142(19981015)83:8<1626::AID-CNCR19>3.0.CO;2-Y.CrossRefPubMed
4.
Arevalo JC, Wu SH: Neurotrophin signaling: many exciting surprises!. Cell Mol Life Sci. 2006, 63: 1523-37. 10.1007/s00018-006-6010-1.CrossRefPubMed
5.
Nakagawara A: Neural crest development and neuroblastoma: the genetic and biological link. Prog Brain Res. 2004, 146: 233-42.PubMed
6.
Nakagawara A: Trk receptor kinases: a bridge between cancer and neural development. Cancer Lett. 2001, 169: 107-14. 10.1016/S0304-3835(01)00530-4.CrossRefPubMed
7.
Bampton ET, Taylor JS: Effects of Schwann cell secreted factors on PC12 cell neuritogenesis and survival. J Neurobiol. 2005, 63: 29-48. 10.1002/neu.20119.CrossRefPubMed
8.
Eggert A, Ikegaki N, Liu X, Chou TT, Lee VM, Trojanowski JQ, Brodeur GM: Molecular dissection of Trk-A signal transduction pathways mediating differentiation in human neuroblastoma. Oncogene. 2000, 19: 2043-51. 10.1038/sj.onc.1203518.CrossRefPubMed
9.
Weier HU, Rhein AP, Shadravan F, Collins C, Polikoff D: Rapid physical mapping of the human trk protooncogene (NTRK1) to human chromosome 1q21-q22 by P1 clone selection, fluorescence in situ hybridization (FISH) and computer-assisted microscopy. Genomics. 1995, 26: 390-3. 10.1016/0888-7543(95)80226-C.CrossRefPubMed
10.
Greco A, Mariani C, Miranda C, Pagliardini S, Pierotti MA: Characterization of the NTRK1 genomic region involved in chromosomal rearrangements generating TRK oncogenes. Genomics. 1993, 18: 397-400. 10.1006/geno.1993.1482.CrossRefPubMed
11.
Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T, Ries RE, Lubman O, Fremont D, McLellan MD, Payton JE, Westervelt P, DiPersio JF, Link DC, Walter MJ, Graubert TA, Watson M, Baty J, Heath S, Shannon WD, Nagarajan R, Bloomfield CD, Mardis ER, Wilson RK, Ley TJ: Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood. 2008, 111: 4797-808. 10.1182/blood-2007-09-113027.CrossRefPubMedPubMedCentral
12.
Marchetti A, Felicioni L, Pelosi G, Del Grammastro M, Fumagalli C, Sciarrotta M, Malatesta S, Chella A, Barassi F, Mucilli F, Camplese P, D'Antuono T, Sacco R, Buttitta F: Frequent mutations in the neurotrophic tyrosine receptor kinase gene family in large cell neuroendocrine carcinoma of the lung. Hum Mutat. 2008, 29: 609-16. 10.1002/humu.20707.CrossRefPubMed
13.
Scaruffi P, Cusano R, Dagnino M, Tonini GP: Detection of DNA polymorphisms and point mutations of high-affinity nerve growth factor receptor (TrkA) in human neuroblastoma. Int J Oncol. 1999, 14: 935-8.PubMed
14.
Gimm O, Greco A, Hoang-Vu C, Dralle H, Pierotti MA, Eng C: Mutational analysis reveals novel sequence variants in NTRK1 in sporadic human medullary thyroid carcinoma. J Clin Endocrinol Metab. 1999, 84: 2784-87. 10.1210/jc.84.8.2784.PubMed
15.
George DJ, Suzuki H, Bova GS, Isaacs JT: Mutational analysis of the TrkA gene in prostate cancer. Prostate. 1998, 36: 172-80. 10.1002/(SICI)1097-0045(19980801)36:3<172::AID-PROS5>3.0.CO;2-J.CrossRefPubMed
16.
Indo Y: Genetics of congenital insensivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Clin Auton Res. 2002, 12 (Suppl 1): I20-I32. 10.1007/s102860200016.CrossRefPubMed
17.
Schramm A, Schulte JH, Astrahantseff K, Apostolov O, Limpt V, Sieverts H, Kuhfittig-Kulle S, Pfeiffer P, Versteeg R, Eggert A: Biological effects of TrkA and TrkB receptor signaling in neuroblastoma. Cancer Lett. 2005, 228: 143-53. 10.1016/j.canlet.2005.02.051.CrossRefPubMed
18.
Ratajska M, Brozek I, Senkus-Konefka E, Jassem J, Stepnowska M, Palomba G, Pisano M, Casula M, Palmieri G, Borg A, Limon J: BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland. Oncol Rep. 2008, 19: 263-8.PubMed
19.
20.
21.
22.
Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005, 21: 263-5. 10.1093/bioinformatics/bth457.CrossRefPubMed
23.
Till JH, Becerra M, Watty A, Lu Y, Ma Y, Neubert TA, Burden SJ, Hubbard SR: Crystal structure if the MuSK tyrosine kinase: insights into receptor autoregulation. Structure. 2002, 10: 1187-96. 10.1016/S0969-2126(02)00814-6.CrossRefPubMed
24.
Mosse YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport E, Devoto M, Maris JM: Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008, 455: 930-935. 10.1038/nature07261.CrossRefPubMedPubMedCentral
25.
Serra A, Haberle B, Konig IR, Kappler R, Suttorp M, Schackert HK, Roesner D, Fitze G: Rare occurrence of PHOX2b mutations in sporadic neuroblastomas. J Pediatr Hematol Oncol. 2008, 30: 728-32. 10.1097/MPH.0b013e3181772141.CrossRefPubMed
26.
Gerhardus A, Schleberger H, Schlegelberger B, Gadzicki D: Diagnostic accuracy of methods for the detection of BRCA1 and BRCA2 mutations: a systematic review. Eur J Hum Genet. 2007, 15: 619-27. 10.1038/sj.ejhg.5201806.CrossRefPubMed
27.
Hoehner JC, Olsen L, Sandstedt B, Kaplan DR, Pahlman S: Association of neurotrophin receptor expression and differentiation in human neuroblastoma. Am J Pathol. 1995, 147: 102-12.PubMedPubMedCentral
28.
Mardy S, Miura Y, Endo F, Matsuda I, Indo Y: Congenital insensitivity to pain with anhydrisis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor. Hum Mol Genet. 2001, 10: 179-88. 10.1093/hmg/10.3.179.CrossRefPubMed
29.
Spix C, Pastore G, Sankla R, Stiller CA, Steliaroua-Foucher E: Neuroblastoma incidence and survival in European children (1978-1997). Report from Automated Childchood Cancer Information System project. Eur J Cancer. 2006, 42: 2081-2091. 10.1016/j.ejca.2006.05.008.CrossRefPubMed
30.
Cattelani S, Defferrari R, Marsilio S, Bussolari R, Candini O, Corradini F, Ferrari-Amorotti G, Guerzoni C, Pecorari L, Menin C, Bertorelle R, Altavista P, McDowell HP, Boldrini R, Dominici C, Tonini GP, Raschellà G, Calabretta B: Impact of a single nucleotide polymorphism in the MDM2 gene on neuroblastoma development and aggressiveness: results of a pilot study on 239 patients. Clin Cancer Res. 2008, 14: 3248-3253. 10.1158/1078-0432.CCR-07-4725.CrossRefPubMed
31.
de Pablo Y, Perez-Garcia MJ, Georgieva MV, Sanchis D, Lindqvist N, Soler RM, Comella JX, Llovera M: Tyr-701 is a new regulatory site for neurotrophin receptor TrkA trafficking and function. J Neurochem. 2008, 104: 124-39.PubMed
32.
Humphrey W, Dalke A, Schulten K: VMD - Visual Molecular Dynamics. J Mol Graph. 1996, 14 (1): 33-38. 10.1016/0263-7855(96)00018-5.CrossRefPubMed
Metadata
Title
c.1810C>T Polymorphism of NTRK1Gene is associated with reduced Survival in Neuroblastoma Patients
Authors
Beata S Lipska
Elżbieta Drożynska
Paola Scaruffi
Gian Paolo Tonini
Ewa Iżycka-Świeszewska
Szymon Ziętkiewicz
Anna Balcerska
Danuta Perek
Alicja Chybicka
Wojciech Biernat
Janusz Limon
Publication date
01-12-2009
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2009
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-9-436

Other articles of this Issue 1/2009

BMC Cancer 1/2009 Go to the issue

Research article

Bioelectrical impedance phase angle in clinical practice: implications for prognosis in stage IIIB and IV non-small cell lung cancer

Research article

Polymorphisms in NF-κB Inhibitors and Risk of Epithelial Ovarian Cancer

Research article

Inverse correlation between PDGFC expression and lymphocyte infiltration in human papillary thyroid carcinomas

Research article

Identification of hematein as a novel inhibitor of protein kinase CK2 from a natural product library

Research article

Presence of activating KRAS mutations correlates significantly with expression of tumour suppressor genes DCN and TPM1 in colorectal cancer

Research article

Alterations of BCCIP, a BRCA2 interacting protein, in astrocytomas
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