Genomic Profiling And Clininc Study In Primary Central Nervous System Lymphoma

The term primary central nervous system (CNS) lymphoma (PCNSL) currentlyrefers to lymphomas arising exclusively in the CNS, that is, the brain parenchyma,spinalcord, eyes, cranial nerves and/or meninges. The incidence of PCNSL inimmunocompetent patients has significantly increased during the last decades, thus,necessitating studies addressing the biology,pathogenesis and therapy in order toimprove the still poor prognosis as compared with lymphoma at other sites.Approximately95%of PCNSL are mature non-Hodgkin B-cell lymphomas,morphologically indistinguishable from systemic diffuse large B-cell lymphoma(DLBCL) of other organs.PCNSL is an aggressive brain tumour, representing3%ofintracranial neoplasms and4%~6%of extranodal lymphomas with a yearly incidenceof0.5cases per100000people and with a median survival, if untreated, of1.5~3.3months. The incidence of PCNSL in the past two decades has risen inimmunocompetent individuals,especially in those>50years of age. Median age atdiagnosis is60–65years, and median survival is10~20months, with survival of<20%~30%at5years.PCNSL typically presents as an intra-cranial mass lesion, usually with acombination of generalized symptoms such as headache, confusion and lethargy, aswell as lateralizing symptoms such as hemiparesis. Computed tomography(CT) scansand magnetic resonance imaging (MRI) typically show unique or multipleperiventricular, homogeneously enhancing lesions. But PCNSL is potentiallyassociated with a large spectrum of radiological presentations and can simulateinflammatory (sarcoidosis, multiple sclerosis) or infectious (acute disseminatedencephalomyelitis)diseases or other brain tumors (meningiomas, malignant gliomas,gliomatosis cerebri, brain metastases). At present,most studies of PCNSL havefocused on the radiological feature,pathology,as well as a little cohort clinical study ofpatients in civil. Little is known about the tumorigenesis of PCNSL.The purpose of the first section study was to asses the clinical feautres,neuroradiological findings,phatology,and to investigate pathogenesis of PCNSL andto identiyfy prognostic marker in a large cohort of patients with PCNSL in China. Insecond section study, we applied high resolution array-based comparative genomichybridization (aCGH) to a panel of PCNSL samples from patients and peripheralblood lymph cell samples from healthy men to obtain a genomic profile of PCNSL.Thus,we will obtain the differential gene. From these, we selected candidate genes inwhich expression changes were associated with copy number aberrations. Inaddition,gene ontology was performed with FUN softway to identify identifypathways specifically affected in PCNSL, a pathway analysis of the PCNSL geneexpression dataset was performed. The identified genes were validated usingquantitative real-time reverse-transcribed polymerase chain reaction (RT-PCR). Newstrategies will not only benefit from advances in the management of NHL outside theCNS but also from a better understanding of specific PCNSL tumorigenesis.From June2005to December2011,122consecutive PCNSL patients with computed tomography(CT) and/or magnetic resonance imaging (MRI)(medianage,53.6years) were enrolled onto a radiological study of the fist sention. Amongthose patients,95cases was investigated in pathological data. Clinical data and severalprognostic factors from67PCNSLs were analyzed retrospectively.This study involved50female and72male patients with a median age of53.6years (range5~83years). All tumors available for review were classic diffusenon-Hodgkin's lymphoma, for which the phenotype was determined in95patients:86(90.5%) were B-cell and2(2.2%) were T-cell type tumors. According to theWH0(2008) classification of lymphoid neoplasms, most lesions were diffuse large celltumors. A total of2008tumors were reviewed in122patients for whom preoperativecomputerized tomography and magnetic resonance studies were available. There wasa single lesion in55.0%of the cases, with a supratentorial location in89.4%. Tumorlocation in the basal ganglia, corpus callosum, or fornix, infiltration of theperiventricular ependyma, or a mirror pattern, were strongly suggestive of a lesion oflymphomatous origin. The histological diagnosis was obtained after biopsy samplingin120patients, with the remainder undergoing surgical resection only. Of the67patients studied,42(62.7%) received chemotherapy plus radiation therapy,25(37.3%)received chemotherapy alone.Using univariate analysis, the authors determined prognostic factors that weresignificantly associated with a favorable impact on survival including age youngerthan60years, Karnofsky Performance Scale(KPS) score larger than70. Expression ofBCL-6was significantly associated with shorter overall survival. Multivariateanalysis was used to confirm the independent prognostic value of (KPS) score and age.Chemotherapy plus radiation therapy does not show more beneficial with a favorableimpact on survival than chemotherapy alone. BCL-6warrants further investigation asa potentially important prognostic marker was an unfavorable prognostic factor.We analyzed a total of6PCNSL samples with high-resolution arraybasedcomparative genomic hybridization from peripheral blood lymph cell samples from6healthy men and performed RT-PCR in4of the6samples. We compiled the top14962genes (z-SCORE=4) showing the greatest differential expression betweenPCNSL and normal lymph cell of peripheral blood. Using gene set enrichmentanalysis, we identified several signal transduction pathways, such as Januskinase-signal and NF-kB transducers and activators of transcription pathway andEMC-adhesionrelated pathways, which may be involved in pathogenesis of PCNSL.The most frequent deletion found in4patients (66.7%) occurred in4q21.2containing BMP2. In conclusion,this study identified novel tumor gene(sBMP2)thatmay serve as therapeutic targets of PCNSL.