O’Neill, Brian Patrick

Abstract Purpose: Glioblastoma is a devastating, incurable disease with few known prognostic factors. Here, we present the first genome-wide survival and validation study for glioblastoma. Experimental Design: Cox regressions for survival with 314,635 inherited autosomal single-nucleotide polymorphisms (SNP) among 315 San Francisco Adult Glioma Study patients for discovery and three independent validation data sets [87 Mayo Clinic, 232 glioma patients recruited from several medical centers in Southeastern United States (GliomaSE), and 115 The Cancer Genome Atlas patients] were used to identify SNPs associated with overall survival for Caucasian glioblastoma patients treated with the current standard of care, resection, radiation, and temozolomide (total n = 749). Tumor expression of the gene that contained the identified prognostic SNP was examined in three separate data sets (total n = 619). Genotype imputation was used to estimate hazard ratios (HR) for SNPs that had not been directly genotyped. Results: From the discovery and validation analyses, we identified a variant in single-stranded DNA-binding protein 2 (SSBP2) on 5q14.1 associated with overall survival in combined analyses (HR, 1.64; P = 1.3 × 10−6). Expression of SSBP2 in tumors from three independent data sets also was significantly related to patient survival (P = 5.3 × 10−4). Using genotype imputation, the SSBP2 SNP rs17296479 had the strongest statistically significant genome-wide association with poorer overall patient survival (HR, 1.79; 95% CI, 1.45-2.22; P = 1.0 × 10−7). Conclusion: The minor allele of SSBP2 SNP rs17296479 and the increased tumor expression of SSBP2 were statistically significantly associated with poorer overall survival among glioblastoma patients. With further confirmation, previously unrecognized inherited variations influencing survival may warrant inclusion in clinical trials to improve randomization. Unaccounted for genetic influence on survival could produce unwanted bias in such studies. Clin Cancer Res; 18(11); 3154–62. ©2012 AACR.

Abstract Purpose: Only a limited number of genetic studies have been conducted in primary central nervous system lymphomas (PCNSL), partly due to the rarity of the tumors and the very limited amount of available tissue. In this report, we present the first molecular characterization of copy number abnormalities (CNA) of newly diagnosed PCNSL by array-based comparative genomic hybridization (aCGH) in formalin-fixed paraffin-embedded (FFPE) specimens and compare the results with matched, frozen tumor specimens. Experimental Design: We conducted aCGH in FFPE tissues from PCNSL. Results were compared with matched, paired, frozen tumors. Results: Our analysis confirmed the good to fair quality and reliability of the data generated from limited amounts of tumoral FFPE tissue. Overall, all PCNSL cases were characterized by highly complex karyotypes, with a median of 23 CNAs per patient (range, 17–47). Overall, 20 chromosomal regions were recurrently found in more than 40% of cases. Deletions of 6p21, 6q, and 9p21.3 and gain of 12q12-q24.33 were the commonest CNAs. Other minimal affected regions were defined, and novel recurrent CNAs affecting single genes were identified in 3q26.32 (TBL1XR1) and 8q12.1 (TOX). Conclusions: The results obtained are encouraging. Larger archival tissue collections can now be analyzed to complement the still fragmented knowledge we have of the genetic basis of the PCNSL. Clin Cancer Res; 17(13); 4245–53. ©2011 AACR.

Abstract Two patients who had focal neurological deficits as the initial manifestation of a malignant non-Hodgkin's lymphoma involving the skull are described. Soft-tissue masses and variable bone destruction were the predominant computed tomographic findings, and magnetic resonance imaging studies revealed meningeal involvement in one case and sinus thrombosis in the other. Malignant non-Hodgkin's lymphomas initially appearing in the skull are rare, but these lesions should be considered in patients with a palpable scalp mass who have focal neurological signs.

Os linfomas primários do SNC são raros, mas sua incidência tem aumentado nos últimos anos, Estes tumores frequentemente se localizam nos gânglios da base e tálamo ou se apresentam de forma multifocal. O tratamento atual para eles é a radioterapia, associada ou não a quimioterapia. Devido à sua extremamente baixa morbidade, a biópsia estereo-táxica é o método ideal para determinar o diagnóstico histológico em pacientes com suspeita de linfomas do SNC. Os autores apresentam estudo de 49 casos de linfomas primários do SNC, diagnosticado por biópsia estereotáxica.

Abstract Introduction. PCNSL is an aggressive primary brain tumor characterized by a perivascular accumulation of malignant cells that have lymphoid characteristics. As there is significantly less information regarding the molecular pathogenesis of PCNSL in comparison with systemic lymphomas the aim of this study was to perform a comprehensive high-resolution genomic analysis in a cohort of PCNSL cases to better characterize the disease at chromosomal and gene level. Material and Methods. Specimens from 7 EBV- and HIV-negative and presumed immunocompetent PCNSL patients with sufficient frozen tissue for DNA extraction were studied. Copy-number abnormalities were analyzed by array CGH using SurePrint G3 (1 million probes) microarray (Agilent). B-cell differentiation status was characterized by immunostains for CD10, MUM-1, and CD138. Results. PCNSL cases were characterized by highly complex genomes with a median of 23 copy-number abnormalities per patient (range 16-49). Twenty-four chromosomal regions were affected in recurrent deletions and 19 in copy-number gains. Gain of 12q12-q24.33 and losses of 9p21.3 and 6q were the most common abnormalities, found in five of the seven patients. There was not a deleted region on 6q unique to all cases, with 6q14.1-q14.3, 6q16.3-q22.2 and 6q25.3-q26 losses being found in 4 out of 5 cases with 6q deletions. Two regions of interest were biallelically deleted. CDKN2A was the sole gene included in all cases with 9p21.3, being biallelically deleted in two out of 5 cases. TOX and CD58, genes associated with the development and activation of T cells, were also biallelically affected. Focal monoallelic deletions affecting negative regulators of the NFkB signaling pathway (MAP4K1, TANK, TAX1BP1, TRIB3), cell cycle (RB1) and immune-cell regulation (SIRPB1, CBLB, NFATC2) were also identified. Overall, a total of 22 genes were included in homozygous deletions in at least one case. Several chromosomal breakpoints were identified inside genes that encode transcription factors previously identified as being part of fusion protein in other hematological malignancies (FOXP1, ETV6 and NCOA2). Conclusion. This pilot study showed evidence for a highly complex genome, mainly characterized by abnormalities affecting a plethora of genes involved in lymphocyte development, activation and NF-kB signaling pathways regulation. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 331.

Abstract Patients with glioblastoma (GBM) exhibit profound systemic immune defects that affect the success of traditional and immune-based treatments. A better understanding of the contribution of the tumor and therapy on systemic and local immune suppression is necessary to improve immune based therapies and monitor the effects of conventional and novel therapies. To identify possible sources of immunosuppression, we measured the constituents of circulating immunity in newly diagnosed and recurrent GBM patients with or without dexamethasone treatment. We identified dexamethasone dependent and independent changes in systemic immunity associated with GBM. Of note, we identified a profound lymphopenia associated with dexamethasone treatement that manifested itself in the T cell compartment with targeted effects on the CD4+ T cells. In addition, we identified tumor and dexamethasone dependent altered monocyte phenotypes. The major population of altered monocytes (CD14+HLA-DRlo/neg) inhibited T cell proliferation, was unable to fully differentiate into mature dendritic cells, was associated with dexamethasone-mediated changes in CCL2 levels, and could be re-created in vitro using tumor supernatants. Interestingly, CD14+HLA-DRlo/neg monocytes were elevated similarly in newly diagnosed and recurrent patients. These data demonstrate that both tumor and steroids contribute to systemic immunosuppression. We provide evidence that tumors express high levels of the monocyte recruitment chemokine CCL2, can contain high numbers of CD14+ cells, that tumor supernatants can transform CD14+HLA-DR+ cells into CD14+HLA-DRlo/neg immune suppressors, and that dexamethasone reduces CCL2 in vitro and is correlated with reduction of CCL2 in vivo. Consequently, we have developed a model for tumor mediated systemic immune suppression via recruitment and transformation of CD14+ cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5303.