Biology subjects

Barnholtz-Sloan, J.

Publications and source records attributed to Barnholtz-Sloan, J..

4 recordsLinked to original sources

bioRxiv2022

Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas

BackgroundHomozygous loss of CDKN2A/B is a genetic alteration found in many cancer types including meningiomas, where it is associated with poor clinical outcome. It is now also a diagnostic criterion for grade 3 meningiomas in the 2021 WHO classification for central nervous system tumors. However, as in other cancers, the relationship between copy number loss of CDKN2A/B and expression of its gene product is unclear and may be either commensurate or paradoxical in nature. Therefore, we aimed to investigate the association of CDKN2A mRNA expression with clinical prognosis, WHO grade, and other molecular biomarkers in meningiomas such as DNA methylation, molecular group, and proteomics. MethodsWe used multidimensional molecular data of 490 meningioma samples from 4 independent cohorts to examine the relationship between mRNA expression of CDKN2A and copy number status, its correlation to clinical outcome, the transcriptomic pathways altered in differential CDKN2A expression, and its relationship with DNA methylation, and proteomics using an integrated molecular approach. ResultsMeningiomas without any copy number loss were dichotomized into high (CDKN2Ahigh) and low (CDKN2Alow) CDKN2A mRNA expression groups. Patients with CDKN2Ahigh meningiomas had poorer progression free survival (PFS) compared to those with CDKN2Alow meningiomas. CDKN2A mRNA expression was increased in more aggressive molecular groups, and in higher WHO grade meningiomas across all cohorts. CDKN2Ahigh meningiomas and meningiomas with CDKN2A copy number loss shared common up-regulated cell cycling pathways. CDK4 mRNA expression was increased in CDKN2Ahigh meningiomas and both p16 and CDK4 protein were more abundant in CDKN2Ahigh meningiomas. CDKN2Ahigh meningiomas were frequently hypermethylated at the gene body and UTR compared to CDKN2Alow meningiomas and found be more commonly Rb-deficient. ConclusionsAn intermediate level of CDKN2A mRNA expression appears to be optimal as significantly low (CDKN2A deleted) or high expression (CDKN2Ahigh) are associated with poorer outcomes clinically. Though CDK4 is elevated in CDKN2Ahigh meningiomas, Rb-deficiency may be more common in this group, leading to lack of response to CDK inhibitors.

cancer biology↗

bioRxiv2019

JAM-A functions as a female microglial tumor suppressor in glioblastoma

Glioblastoma (GBM) remains refractory to treatment. In addition to its cellular and molecular heterogeneity, epidemiological studies indicate the presence of additional complexity associated with biological sex. GBM is more prevalent and aggressive in male compared to female patients, suggesting the existence of sex-specific growth, invasion, and therapeutic resistance mechanisms. While sex-specific molecular mechanisms have been reported at a tumor cell-intrinsic level, sex-specific differences in the tumor microenvironment have not been investigated. Using transgenic mouse models, we demonstrate that deficiency of junctional adhesion molecule-A (JAM-A) in female mice enhances microglia activation, GBM cell proliferation, and tumor growth. Mechanistically, JAM-A suppresses anti-inflammatory/pro-tumorigenic gene activation via interferon-activated gene 202b (Ifi202b) and found in inflammatory zone (Fizz1) in female microglia. Our findings suggest that cell adhesion mechanisms function to suppress pathogenic microglial activation in the female tumor microenvironment, which highlights an emerging role for sex differences in the GBM microenvironment and suggests that sex differences extend beyond previously reported tumor cell intrinsic differences.\n\nSummaryTuraga et al. demonstrate that female microglia drive a more aggressive glioblastoma phenotype in the context of JAM-A deficiency. These findings highlight a sex-specific role for JAM-A and represent the first evidence of sexual dimorphism in the glioblastoma microenvironment.

cancer biology↗

bioRxiv2019

Assessment of Polygenic Architecture and Risk Prediction based on Common Variants Across Fourteen Cancers

We analyzed summary-level data from genome-wide association studies (GWAS) of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) contributing to risk, as well as the distribution of their associated effect sizes. All cancers evaluated showed polygenicity, involving at a minimum thousands of independent susceptibility variants. For some malignancies, particularly chronic lymphoid leukemia (CLL) and testicular cancer, there are a larger proportion of variants with larger effect sizes than those for other cancers. In contrast, most variants for lung and breast cancers have very small associated effect sizes. For different cancer sites, we estimate a wide range of GWAS sample sizes, required to explain 80% of GWAS heritability, varying from 60,000 cases for CLL to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores, compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that polygenic risk scores have substantial potential for risk stratification for relatively common cancers such as breast, prostate and colon, but limited potential for other cancer sites because of modest heritability and lower disease incidence.

genetics↗

bioRxiv2019

Tumor cell phenotype and heterogeneity differences in IDH1 mutant vs wild-type gliomas

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated multiplexed immunofluorescence single cell data for 43 protein markers across cancer hallmarks, in addition to cell spatial metrics, genomic sequencing and magnetic resonance imaging (MRI) quantitative features. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion differ between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. Longer overall survival for IDH1mt glioma patients may reflect generalized altered cellular, molecular, spatial heterogeneity which manifest in discernable radiological manifestations.

genomics↗