Primary identification of genomic markers of drug sensitivity for individualized therapy in 38 children with extracranial malignant solid tumors

Abstract

Objective To identify the significance of genomic markers of drug sensitivity for individualized therapy in children with extracranial malignant solid tumors. Methods The surgical specimens and peripheral blood samples in 38 children with refractory extracranial malignant solid tumors were collected between Apri.2011 and Apri.2013.The genomic markers of anticancer drug sensitivity were examined, including gene expression or mutation of 15 chemotherapeutic agents and two targeted drugs by methods of immunohistochemical staining, enzyme linked immunosorbent assay, fluorescence in situ hybridization, polymerase chain reaction amplification and sequencing. Results Among all of 38 samples, 35 were firstly surgical specimens and 3 secondary surgical specimens, and 3 of them were peripheral blood samples.The tumor tissue of the targets for chemotherapeutic agents such as topoisomerase ⅡA (TOPO ⅡA) in 34 cases, Tubulinβ3 in 32 cases, excision repair cross-complementing 1 (ERCC1) in 28 cases, topoisomerase Ⅰ(TOPO Ⅰ) in 28 cases, O6-methylguanine-DNA methyltransferase (MGMT) in 20 cases, thymidylate synthase (TS) in 13 cases and ribonucleotide reductase M1 (RRM1)in 6 cases were examined.The 68.75% samples were fluo-rouracil and pemetrexed sensitivity, 66.67% samples gemcitabine sensitivity, 56.25% samples vincristine(VCR) sensitivity; while 67.65% had low sensitivity to anthracycline/etoposide, 64.29% had low sensitivity to platinum and topotecan/irinotecan; 63.64% had low sensitivity to temozolomide(TMZ). What's more, the peripheral blood of the targets for chemotherapeutic agents such as CYP2C9*3 genotypes in 33 cases and dihydrofolate reductase (DHFR C829T) genotypes in 14 cases were detected, and found that 100.00% and 93.33% of samples had cyclophosphamide and methotrexate sensitivity, respectively.Furthermore, peripheral blood was used to test the targets for chemotherapy toxicity and found that 100.00% of cyclophosphamide and methotrexate toxicity were weak, 76.19% of irinotecan and etoposide toxicity was weak.Additionally, tumor tissues of the genomic markers for targeted drugs, such as vascular endothe-lial growth factor receptor -2 (VEGFR-2) in 15 cases, epidermal growth factor receptor (EGFR) in 5 cases and intercellular cell adhesion molecule-1 in 10 cases, were examined.Up to 68.00% samples were detected sensitive to Bevacizumab.EGFR was not amplified in any case studied and Tyrosine kinase inhibitor response was invalid.On the basis of the above test results, therapeutic strategy for the patients who had unsatisfactory curative effect and then they achieved preliminary effect were promptly adjusted. Conclusions This study firstly examined the genomic markers of drug sensitivity in children with extracranial malignant solid tumors, which provide laboratory basis for individualized treatment selection and drug side effects prediction. Key words: Child; Extracranial malignant solid tumors; Genomic markers of drug sensitivity; Individualized therapy