Purpose Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the CNS. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. Experimental design We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. Results Biallelic inactivation of TOX and PRKCD were recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. Additionally, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11 and translocations IgH-BCL6. Overall, BCR/TLR/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. Conclusions In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas.

Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82×10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48×10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83×10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.

Childhood acute lymphoblastic leukemia (ALL) (age 0–14 years) is 20% more common in Latino Americans than non-Latino whites. We conduct a genome-wide association study in a large sample of 3263 Californian children with ALL (including 1949 of Latino heritage) and 3506 controls matched on month and year of birth, sex, and ethnicity, and an additional 12,471 controls from the Kaiser Resource for Genetic Epidemiology Research on Aging Cohort. Replication of the strongest genetic associations is performed in two independent datasets from the Children’s Oncology Group and the California Childhood Leukemia Study. Here we identify new risk loci on 17q12 near IKZF3/ZPBP2/GSDMB/ORMDL3, a locus encompassing a transcription factor important for lymphocyte development (IKZF3), and at an 8q24 region known for structural contacts with the MYC oncogene. These new risk loci may impact gene expression via local (four 17q12 genes) or long-range (8q24) interactions, affecting function of well-characterized hematopoietic and growth-regulation pathways.

Small heat shock proteins (sHsps) are molecular chaperones that protect cells from cytotoxic effects of protein misfolding and aggregation. HspB1, an sHsp commonly associated with senile plaques in Alzheimer's disease (AD), prevents the toxic effects of A␤ aggregates in vitro. However, the mechanism of this chaperone activity is poorly understood. Here, we observed that in two distinct transgenic mouse models of AD, mouse HspB1 (Hsp25) localized to the penumbral areas of plaques. We have demonstrated that substoichiometric amounts of human HspB1 (Hsp27) abolish the toxicity of A␤ oligomers on N2a (mouse neuroblastoma) cells. Using biochemical methods, spectroscopy, light scattering, and microscopy methods, we found that HspB1 sequesters toxic A␤ oligomers and converts them into large nontoxic aggregates. HspB1 was overexpressed in N2a cells in response to treatment with A␤ oligomers. Cultured neurons from HspB1-deficient mice were more sensitive to oligomer-mediated toxicity than were those from wild-type mice. Our results suggest that sequestration of oligomers by HspB1 constitutes a novel cytoprotective mechanism of proteostasis. Whether chaperone-mediated cytoprotective sequestration of toxic aggregates may bear clues to plaque deposition and may have potential therapeutic implications must be investigated in the future.