Search

Supplemental Digital Content is Available in the Text.

IMPORTANCE: African Americans have the highest breast cancer mortality rate. Although racial difference in the distribution of intrinsic subtypes of breast cancer is known, it is unclear if there are other inherent genomic differences that contribute to the survival disparities. OBJECTIVES: To investigate racial differences in breast cancer molecular features and survival and to estimate the heritability of breast cancer subtypes. DESIGN, SETTING, AND PARTICIPANTS: Among a convenience cohort of patients with invasive breast cancer, breast tumor and matched normal tissue sample data (as of September 18, 2015) were obtained from The Cancer Genome Atlas. MAIN OUTCOMES AND MEASURES: Breast cancer–free interval, tumor molecular features, and genetic variants. RESULTS: Participants were 930 patients with breast cancer, including 154 black patients of African ancestry (mean [SD] age at diagnosis, 55.66 [13.01] years; 98.1% [n = 151] female) and 776 white patients of European ancestry (mean [SD] age at diagnosis, 59.51 [13.11] years; 99.0% [n = 768] female). Compared with white patients, black patients had a worse breast cancer-free interval (hazard ratio, HR=1.67; 95% CI, 1.02-2.74; P = .043). They had a higher likelihood of basal-like (odds ratio, 3.80; 95% CI, 2.46-5.87; P < .001) and human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])–enriched (odds ratio, 2.22; 95% CI, 1.10-4.47; P = .027) breast cancer subtypes, with the Luminal A subtype as the reference. Blacks had more TP53 mutations and fewer PIK3CA mutations than whites. While most molecular differences were eliminated after adjusting for intrinsic subtype, the study found 16 DNA methylation probes, 4 DNA copy number segments, 1 protein, and 142 genes that were differentially expressed, with the gene-based signature having an excellent capacity for distinguishing breast tumors from black vs white patients (cross-validation C index, 0.878). Using germline genotypes, the heritability of breast cancer subtypes (basal vs nonbasal) was estimated to be 0.436 (P = 1.5 × 10−14). The estrogen receptor–positive polygenic risk score built from 89 known susceptibility variants was higher in blacks than in whites (difference, 0.24; P = 2.3 × 10−5), while the estrogen receptor–negative polygenic risk score was much higher in blacks than in whites (difference, 0.48; P = 2.8 × 10−11). CONCLUSIONS AND RELEVANCE: On the molecular level, after adjusting for intrinsic subtype frequency differences, this study found a modest number of genomic differences but a significant clinical survival outcome difference between blacks and whites in The Cancer Genome Atlas data set. Moreover, more than 40% of breast cancer subtype frequency differences could be explained by genetic variants. These data could form the basis for the development of molecular targeted therapies to improve clinical outcomes for the specific subtypes of breast cancers that disproportionately affect black women. Findings also indicate that personalized risk assessment and optimal treatment could reduce deaths from aggressive breast cancers for black women.

Findings reveal a novel basis for protecting CNS neurons against Aβ oligomers (AβOs), neurotoxins believed to instigate neural damage leading to Alzheimer’s dementia. Results with spatially separated cocultures of astrocytes and hippocampal neurons show an exosome-like mechanism by which insulin/IGF1 from astrocytes clear bound AβOs from neuronal surfaces.

The prevailing circuit model predicts that hyperactivity of the striatopallidal pathway and subsequently increased inhibition of external globus pallidus (GPe) neurons lead to the hypokinetic symptoms of Parkinson’s disease (PD). It is believed that hyperactivity of the striatopallidal pathway is due to inactivity of dopamine receptors on the somatodendritic membrane of striatopallidal neurons, but the exact cellular underpinnings remain unclear. In this study, we show that mouse GPe astrocytes critically control ambient glutamate level, which in turn gates striatopallidal transmission via the activation of presynaptic metabotropic glutamate receptors. This presynaptic inhibition of striatopallidal transmission is diminished after the chronic loss of dopamine. Elevation of intracellular glutamate content in astrocytes restores the proper regulation of the striatopallidal input in PD models. These findings argue that astrocytes are key regulators of the striatopallidal synapse. Targeting this cell class may serve as an alternative therapeutic strategy for PD.

Haem is an iron-containing cofactor required for life. Many cellular processes rely on haem and failure to maintain iron homeostasis results in numerous pathological conditions. A study now identifies a Caenorhabditis elegans inter-organ signalling pathway in which secreted intestinal HRG-7 and neuronally secreted BMP signals coordinate animal haem homeostasis.

Background: CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumor suppressors. Currently, for most cancers including gastric cancer (GC), mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs. Results: We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that CBSepimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of CBSin normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles, CBSloss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulfide (H2S), with concomitant increase in NF-κB activity. In a murine genetic model of CBSdeficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach. Conclusions: Our results implicate CBSas a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H2S donors as a potential new therapy for CBS-silenced lesions.

P granules are cytoplasmic structures of unknown function that are associated with germ nuclei in the C. elegans gonad, and are localized exclusively to germ cells, or germ cell precursors, throughout the life cycle. All the known protein components of P granules contain putative RNA- binding motifs, suggesting that RNA is involved in either the structure or function of the granules. However, no specific mRNAs have been identified within P granules in the gonad. We show here that P granules normally contain a low level of RNA, and describe conditions that increase this level. We present evidence that several, diverse mRNAs, including pos-1, mex-1, par-3, skn-1, nos-2 and gld- 1 mRNA, are present at least transiently within P granules. In contrast, actin and tubulin mRNA and rRNA are either not present in P granules, or are present at relatively low levels. We show that pgl-1 and the glh (Vasa-related) gene family, which encode protein components of P granules, do not appear essential for RNA to concentrate in P granules; these proteins may instead function in events that are a prerequisite for RNAs to be transported efficiently from the nuclear surface.

The germ cells, and germ cell precursors, in the nematode Caenorhabditis eleganscontain distinctive granules called P granules. During early embryogenesis, P granules are segregated asymmetrically into those blastomeres that eventually produce the germ line. Because of the correlation between P granule distribution and the development of the germ line, P granules are widely thought to function in some aspect of germ line specification or differentiation. Most of the analysis of P granule structure and localization has focused on the early embryo, when P granules are located in the cytoplasm. However, during most of development P granules are associated with germ cell nuclei. We report here an ultrastructural analysis of the nuclear-associated P granules in the germ cells of the adult hermaphrodite gonad. We show that P granules are tightly associated with nuclear pores and that the positions of certain structures within the P granules correspond to the positions of pores on the nuclear envelope. We present immunocytochemical and ultrastructural data suggesting that P granules can associate, or remain associated, with pore-like structures even after they detach from the nuclear envelope during oogenesis. Finally, we show that nuclear-associated P granules in the gonad contain RNA, complementing previous studies showing that cytoplasmic P granules in embryos contain RNA.

Insect axis formation is best understood in Drosophila melanogaster, where rapid anteroposterior patterning of zygotic determinants is directed by maternal gene products. The earliest zygotic control is by gap genes, which determine regions of several contiguous segments and are largely conserved in insects. We have asked genetically whether early zygotic patterning genes control similar anteroposterior domains in the parasitoid wasp Nasonia vitripennis as in Drosophila. Nasonia is advantageous for identifying and studying recessive zygotic lethal mutations because unfertilized eggs develop as males while fertilized eggs develop as females. Here we describe recessive zygotic mutations identifying three Nasonia genes: head only mutant embryos have posterior defects, resembling loss of both maternal and zygotic Drosophila caudal function; headless mutant embryos have anterior and posterior gap defects, resembling loss of both maternal and zygotic Drosophila hunchback function; squiggy mutant embryos develop only four full trunk segments, a phenotype more severe than those caused by lack of Drosophila maternal or zygotic terminal gene functions. These results indicate greater dependence on the zygotic genome to control early patterning in Nasonia than in the fly.