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Open Access Research article

c.1810C>T Polymorphism of NTRK1 Gene is associated with reduced Survival in Neuroblastoma Patients

Beata S Lipska12*, Elżbieta Drożynska2, Paola Scaruffi3, Gian Paolo Tonini3, Ewa Iżycka-Świeszewska4, Szymon Ziętkiewicz5, Anna Balcerska2, Danuta Perek6, Alicja Chybicka7, Wojciech Biernat8 and Janusz Limon1

Author Affiliations

1 Department of Biology and Genetics, Medical University of Gdańsk, Dębinki 1, 80-211 Gdańsk, Poland

2 Institute of Pediatrics, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland

3 Translational Pediatric Oncology, National Cancer Research Institute, L.go R. Benzi, 10 16132 Genoa, Italy

4 Department of Pathology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland

5 Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology, University of Gdańsk, Kładki 24, 80-822 Gdańsk, Poland

6 Department of Oncology, Memorial Health Institute, Aleja Dzieci Polskich 20, 04-736 Warszawa, Poland

7 Department of Bone Marrow Transplantation, Pediatric Oncology and Hematology, Medical University of Wrocław, Bujwida 44, 50-368 Wrocław, Poland

8 Department of Neuropathology and Molecular Pathology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland

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BMC Cancer 2009, 9:436  doi:10.1186/1471-2407-9-436

Published: 13 December 2009

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.