Myers, R

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Using 32 immune cell surface markers, we identified 23 monocyte clusters in murine blood. Diabetic gastroparesis was associated with a significant decrease in two circulating classical monocyte-like clusters and an upregulation of the Ccr2-Ccl2 axis in the gastric muscularis propria, suggesting increased tissue monocyte migration. This study offers new targets by pointing to a possible role for two classical monocyte subsets connected to the Ccr2- Ccl2 axis.

Abstract Purpose: Multiple myeloma (MM) is the second most common hematological malignancy in the US. It is characterized by a clonal expansion of plasma cells in the bone marrow and extramedullary sites and is preceded by two precursor conditions including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Strong evidence suggests a germline and environmental etiology. However, efforts to characterize heritable changes in gene activity, such as DNA methylation, have not been widely reported. Methods: We examined epigenome-wide DNA methylation as markers of MGUS, SMM and MM in peripheral blood obtained from treatment-naïve European American cases with heavy-chain IgG or IgA MGUS (n=60), SMM (n=31) and MM (n=54) and age- and sex-matched controls (n=79) included from the University of Alabama at Birmingham, University of Chicago and the Mayo Clinic, Rochester [54.5% males; mean age, 64 years (range, 36 to 86)]. We quantified DNA methylation of over 450,000 CpG and non-CpG loci using the Infinium HumanMethylation450 array (Illumina). Differentially methylated positions were calculated using a general linear model framework adjusted for confounders and cellular heterogeneity. Results: A total of 6 CpGs were differentially methylated in MM cases compared to controls at a level of genome-wide statistical significance. MM was associated with hypomethylation at differentially methylated positions inside SBNO2 (P=3.37x10-10), WIZ (P=1.12x10-8), CA6 (P=4.29x10-8) and ADORA1 (P=3.68x10-8) as well as intergenic positions proximal to TNFRSF8 (Chr 1p36.22; P=2.24x10-9) and ENDOV (Chr 17q25.3; P=2.74x10-8). Each of these loci, with the exception of CA6 and ADORA1, were hypomethylated in each of the 3 plasma cell dyscrasia phenotypes including MGUS and SMM and MM cases compared to controls (P<0.03), albeit not at a level of genome-wide statistical significance. Conclusions: These preliminary findings suggest that differences in DNA methylation may contribute to altered risk of MM, as well as its precursor conditions, and may play a role in plasma cell dyscrasia progression as a consequence of heritable changes in gene activity due to past exposures. Replication in a large yet similarly well-characterized population is warranted. Citation Format: Stephen D. Gragg, Devin Absher, Xiangqin Cui, Christina Pillion, Richard Myers, Shaji Kumar, Luciano Costa, Brian Chiu, Celine Vachon, Elizabeth Brown. Epigenome-wide association study reveals differential DNA methylation consistent with progression of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1319. doi:10.1158/1538-7445.AM2017-1319

Abstract Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation. Clin Cancer Res; 21(12); 2722–9. ©2015 AACR. See related article by Paoletti et al., p. 2771