Copy Number Variation Of Peripheral Neuroblastic Tumors And Their Clinicopathologic Implication

ObjectiveTo detect copy number variation(CNV)and the somatic mutations of nine cancer related genes,and to analyze their clinicopathological implication in peripheral neuroblastic tumors(pNTs).Materials and MethodsTwenty-four formalin-fixed and paraffin-embedded pNTs tissues including 16 neuroblastomas(NB)and 8 ganglioneuroblastomas(GNB),and the patient’s corresponding clinicopathologic data were collected.The whole genome copy number variation(CNV)including loss of heterozygosity(LOH)and copy neutral LOH(CNLOH),and the somatic mutations of nine cancer related genes including BRAF,EGFR,IDH1,IDH2,KRAS,NRAS,PIK3 CA,PTEN,TP53 were detected by Affymetrix Oncoscan molecular inversion probe arrays(Oncoscan).Meanwhile,to correlate the molecular aberrations with clinical factors,such as patiant’s age,sex,tumor’s stage,risk,histology,survival time and MYCN status.ResultsOf the 24 pNTs cases,all chromosomes had one or more CNVs,and gains were far more than losses,while gains of chromosome 7 and 17 were more frequent,with occurring in 62.5%(15/24)and 87.50%(21/24)of the pNTs patients respectively.And gain of chromosome arm 17 q was more likely to occur in high risk group.Except for chromosome 18 and Y,the rest twenty-two chromosomes had LOH.Among them,chromosome 1,3,11,16 and X had the top five highest incidence rate of LOH,which were 50%(12/24),66.67%(16/24),37.50%(9/24),95.83%(23/24)and 54.17%(13/24),respectively.The total copy number aberrations of NB were far more than those of GNB(P=0.000).The proven and novel oncogenes(OG)and tumor suppressor genes(TSG)involved in the CNV regions affected the major pathways like Chromatin Modification in 20 cases(83.33%,20/24),RAS pathway in 19 cases(79.17%,19/24),Cell Cycle/Apoptosis pathway in 18 cases(75%,18/24),genome maintenance in 18 cases(75%,18/24),NOTCH pathway in 16 cases(66.67%,16/24),TGF-β pathway in 16 cases(66.67%,16/24),HH pathway in 16 cases(66.67%,16/24),APC pathway in 14 cases(58.33%,14/24),transcriptional regulation pathway in 13 cases(54.17%,13/24),PI3 K pathway in 12 cases(50%,12/24).In addition,we identified that 6 NB cases(25%,6/24)occurred CNLOH,in which related chromosomes included chromosome 5,chromosome 9,chromosome 16,chromosome 19,3p,12 q and 15 q.Our research also showed that,of the 24 pNTs cases,9 cases(37.5%,9/24)occured TP53 mutation,7 cases(29.17%,7/24)showed NRAS mutation,7 cases(29.17%,7/24)presented EGFR mutation,3 cases(12.5%,3/24)occurred KRAS mutation,1 case(4.17%,1/24)occurred PTEN mutation,and 1 case(4.17%,1/24)had PIK3 CA mutation.However,none of pNTs displayed BRAF,IDH1 and IDH2 mutation.As the most common mutated gene,TP53 mutation was not associated with sex,age,clinical stage,risk and survival time in pNTs patients.ConclusionsOncoscan arrays worked very well on FFPE tissues,and could detect the whole genome CNV and the somatic mutations of nine cancer related genes in a single cohort.Meanwhile,it could position the cancer related genes that were involved in chromosome regions of CNV.Peripheral neuroblastic tumors was a series of tumors which had a variety of molecular genetic changes.Copy number variation,especially copy number gain,was the important genetic changes for pNTs,and CNLOH would be special for NB.A few of CNVs had clinicopathological implication.Further research should be followed to confirm the implication of genes and signal transduction pathways involved in regions of CNV in pNTs.