Molecular-genetic markers for diagnosis and prognosis in pediatric solid malignancies

Khranovska N.M., Ionkina N.V., Svergun N.M., Inomistova M.V., Klymnyuk G.I.

N.M. Khranovska, N.V. Ionkina, N.M. Svergun, M.V. Inomistova, G.I. Klymnyuk

National Cancer Institute, Kyiv, Ukraine

Introduction: Molecular-genetic markers are very important tools for diagnosis and prognosis of solid tumors in children. Aim: To study chromosomal translocations in patients with pediatric solid malignancies. Patients and Methods: Study has been performed on 279 tumor specimens, which were collected at diagnosis, and 90 specimens of bone marrow (BM) puncture biopsy from 200 patients with neuroblastoma (NB), 21 — Ewing sarcoma family tumors (ESFT), 29 — alveolar rhabdomyosarcoma (ARMS), 29 — embryonal RMS (ERMS). The study protocol was approved by Ethical Committee permission of National Cancer Institute (Kyiv, Ukraine). Chromosomal translocations were detected by fluorescence in situ hybridization (FISH) or real-time PCR on fresh or paraffin-embedded tissue samples. Results: Chromosomal translocation t(2;13)(q35;q14) exhibiting chimeric PAX3-FKHR and PAX7-FKHR gene products are the hallmarks of the ARMS. PAX-FKHR fusions were detected in 58 RMS samples: 10 (17,3%) had PAX3-FKHR and had 24 (41,4%) PAX7-FKHR fusions, 24 (41,3%) cases were fusion-negative. PAX3-FKHR or PAX7-FKHR fusions were found in all ARMS. PA3/7-FKHR was detected in 5 of 29 patients with eRMS; it indicates the type of mixed type RMS and requires a change of tactics on the protocol for the treatment of ARMS. In addition, PAX3-FKHR fusion products were detected in biopsy tissue and BM from 3 patients. ESFT is associated with chromosomal translocation t(11;22)(q24;q12). Out of the 21 samples with translocations detected, 16 (76.3%) had EWS-FLI1 type 1, 1 (4.7%) had EWS-FLI1 type 2, 2 (9.5%) had EWS-ERG, 2 (9.5%) had EWS-ETV4 translocation. Fusion transcript EWS-FLI1 type 1 was found in BM of 6 patients. The most significant abnormality in NB is amplification of proto-oncogene MYC; its locus lies on the short arm of chromosome 1. In 44 (22%) cases of primary NBs amplification of MYCN gene is present. MYCN gene is a factor of unfavourable prognosis and influences the choice of treatment schedules. One sample with MYCN amp pos and 1p36 del pos, and 3 samples in MYCN amp neg and1p36 del pos were detected. Loss of heterozygosity (LOH) at 1p36 was independently associated with a worse outcome in NB patients. NB expresses the tyrosine hydroxylase (TH) mRNA, the first enzyme in the catecholamine pathway. TH expression was found in BM of 74 (37%) patients with NB. Molecular-genetic testing is more accurate than standard morphological methods; it enables detection of the presence of tumor cells in BM at diagnosis and during treatment, allows optimization of the treatment strategy. Conclusion: Molecular-genetic analysis helps to identify specific genes in children with solid malignancies in order to specify the diagnosis, prognosis; it also influences the selection of at-risk patients and treatment monitoring.

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