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Mutational analysis of primary central nervous system lymphoma.

ABSTRACT: Little is known about the genomic basis of primary central nervous system lymphoma (PCNSL) tumorigenesis. To investigate the mutational profile of PCNSL, we analyzed nine paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Eight genes of interest have been further investigated by focused resequencing in 28 additional PCNSL tumors to better estimate their incidence. Our study identified recurrent somatic mutations in 37 genes, some involved in key signaling pathways such as NFKB, B cell differentiation and cell cycle control. Focused resequencing in the larger cohort revealed high mutation rates for genes already described as mutated in PCNSL such as MYD88 (38%), CD79B (30%), PIM1 (22%) and TBL1XR1 (19%) and for genes not previously reported to be involved in PCNSL tumorigenesis such as ETV6 (16%), IRF4 (14%), IRF2BP2 (11%) and EBF1 (11%). Of note, only 3 somatically acquired SNVs were annotated in the COSMIC database. Our results demonstrate a high genetic heterogeneity of PCNSL and mutational pattern similarities with extracerebral diffuse large B cell lymphomas, particularly of the activated B-cell (ABC) subtype, suggesting shared underlying biological mechanisms. The present study provides new insights into the mutational profile of PCNSL and potential targets for therapeutic strategies.

SUBMITTER: Bruno A

PROVIDER: S-EPMC4148122 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Mutational analysis of primary central nervous system lymphoma.

Bruno Aurélie A Boisselier Blandine B Labreche Karim K Marie Yannick Y Polivka Marc M Jouvet Anne A Adam Clovis C Figarella-Branger Dominique D Miquel Catherine C Eimer Sandrine S Houillier Caroline C Soussain Carole C Mokhtari Karima K Daveau Romain R Hoang-Xuan Khê K

Oncotarget 20140701 13

Little is known about the genomic basis of primary central nervous system lymphoma (PCNSL) tumorigenesis. To investigate the mutational profile of PCNSL, we analyzed nine paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Eight genes of interest have been further investigated by focused resequencing in 28 additional PCNSL tumors to better estimate their incidence. Our study identified recurrent somatic mutations in 37 genes, some involved in key signal ...[more]

PMID: 24970810

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Project description:ImportanceVisual impairment in primary central nervous system lymphoma (PCNSL) is caused mostly by intraocular lymphomatous involvement (vitritis and retinal infiltration), whereas optic nerve infiltration (ONI) is a rare condition.ObjectiveTo describe the clinical presentation of ONI, its imaging characteristics, and outcome.Design, setting and participantsA total of 752 patients diagnosed with PCNSL were retrospectively identified from the databases of 3 French hospitals from January 1, 1998, through December 31, 2014. Of these, 7 patients had documented ONI. Exclusion criteria were intraocular involvement, orbital lymphoma, or other systemic lymphoma. Clinical presentation, neuroimaging, biological features, treatment, and outcomes were assessed.Main outcomes and measuresTreatment response was evaluated clinically and radiologically on follow-up magnetic resonance imaging (MRI) according to the International PCNSL Collaborative Group response criteria.ResultsThe 7 patients included 5 women and 2 men. Median age at diagnosis was 65 years (range, 49-78 years). Two patients had initial ONI at diagnosis, and 5 had ONI at relapse. Clinical presentation was marked by rapidly progressive and severe visual impairment for all patients. The MRI findings showed optic nerve enlargement in 3 patients and contrast enhancement of the optic nerve in all patients. Additional CNS lesions were seen in 4 patients. Examination of cerebrospinal fluid samples detected lymphomatous meningitis in 2 patients. Clinical outcome was poor and marked by partial recovery for 2 patients and persistent severe low visual acuity or blindness for 5 patients. Median progression-free survival after optic nerve infiltration was 11 months (95% CI, 9-13 months), and median overall survival was 18 months (95% CI, 9-27 months).Conclusions and relevanceOptic nerve infiltration is an atypical and challenging presentation of PCNSL. Its visual and systemic prognosis is particularly poor compared with vitreoretinal lymphomas even in response to chemotherapy. Although intraocular involvement is frequent in PCNSL and clinically marked by slowly progressive visual deterioration, lymphomatous ONI is rare and characterized by rapidly progressive severe visual impairment.

Dataset Information

Mutational analysis of primary central nervous system lymphoma.

Publications

Mutational analysis of primary central nervous system lymphoma.

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