Citations

Abstract DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

AbstractBackgroundPrognosis among patients with differentiated thyroid cancer is widely variable. Better understanding of biologic subtypes is necessary to stratify patients and improve outcomes.MethodsIn patients diagnosed with classic histology papillary thyroid cancer treated from 1973 to 2009, BRAF V600E mutation status was determined on surgical tumor specimens by restriction fragment length polymorphism analysis. A tissue microarray (TMA) was constructed from tumor specimens in triplicate and stained by immunohistochemistry for RET, phospho‐MEK, MAPK(dpERK), PPARγ, and phospho‐AKT(pAKT). Stained slides were scored independently and blindly by two investigators and compared to tumor and patient characteristics and outcomes.ResultsA total of 231 patients had archived formalin‐fixed, paraffin‐embedded tumor tissue available and were included on the TMA. Mean age at diagnosis was 44 years (range 6‐82 years); proportion of patients with female sex was (72%); 2015 American Thyroid Association (ATA) risk stratification was low (26%), intermediate (32%), and high (42%). BRAF V600E mutation was found in 74% of specimens, and IHC was scored as positive for RET (61%), MAPK (dpERK) (14%), PPARγ (27%), and pAKT (39%). Positive RET staining was associated with a lower risk of recurrence (HR = 0.46, 95% CI 0.22‐0.96). No other molecular biomarkers were independent predictors of recurrence on univariable analysis. On RPA, patients with RET‐negative and either MAPK(dpERK)‐positive or pAKT‐positive tumors were identified to have a high risk of recurrence (HR = 5.4, 95%CI 2.5‐11.7). This profile remained associated with recurrence in a multivariable model including ATA risk stratification (HR = 2.8, 95% CI 1.3‐6.0).ConclusionCharacterization of molecular pathways involved in cPTC tumorigenesis may add further risk stratification for recurrence beyond the 2015 ATA risk categories alone.

INTRODUCTION The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. RATIONALE We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. RESULTS Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids’ epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs). Several enhancer modules converged with gene modules, suggesting that coexpressed genes are regulated by enhancers with correlated patterns of activity. Furthermore, enhancers active in organoids and fetal brains were enriched for ASD de novo variants that disrupt binding sites of homeodomain, Hes1, NR4A2, Sox3, and NFIX transcription factors. CONCLUSION We validated hiPSC-derived cortical organoids as a suitable model system for studying gene regulation in human embryonic brain development, evolution, and disease. Our results suggest that organoids may reveal how noncoding mutations contribute to ASD etiology. Summary of the study, analyses, and main results. Data were generated for iPSC-derived human telencephalic organoids and isogenic fetal cortex. Organoids modeled embryonic and early fetal cortex and show a larger repertoire of enhancers. Enhancers could be divided into activators and repressors of gene expression. We derived networks of modules and supermodules with correlated gene and enhancer activities, some of which were implicated in autism spectrum disorders (ASD).

Background Patients with tetralogy of Fallot ( TOF ) remain at risk for cardiovascular events despite successful repair. Some of the current risk stratification tools require advanced imaging and invasive studies, and hence are difficult to apply to routine patient care. A recent study showed that QRS fragmentation ( QRS ‐f) is predictive of mortality in patients with TOF. The current study aims to validate this result by assessing whether severity of QRS ‐f could predict all‐cause mortality in a different TOF population. Methods and Results The authors reviewed the Mayo Adult Congenital Heart Disease database for patients with TOF who had ECG from 1990–2017. QRS ‐f was defined as notches in QRS complex in ≥2 contiguous leads on ECG , not related to bundle branch block, and classified as none, mild (≤3 leads), moderate (4 leads), or severe (≥5 leads). Of 465 patients (age 37±14 years) in the study, QRS ‐f was present in 161 (35%): mild (n=43, 9%), moderate (n=77, 17%), and severe (n=41, 9%). There were 55 deaths (12%) during 13.6±8.2 years of follow‐up. Severity of QRS ‐f remained an independent predictor of all‐cause mortality after adjustment for other ECG parameters, patient demographics, and atrial and ventricular arrhythmia (hazard ratio, 1.74 per class; 95% confidence interval, 1.08–2.93 [ P =0.041]). Conclusions The presence of severe QRS ‐f may be used as complementary data to the usual clinical indices to determine whether interventions such as invasive electrophysiology study should be performed in patients with nonsustained ventricular tachycardia or to proceed with pulmonary valve replacement in patients with severe pulmonary regurgitation with ventricular volumes below the guideline‐directed threshold for intervention.

BACKGROUND/OBJECTIVES The incidence of myeloma in older adults is increasing, yet little is known about geriatric impairments in these patients. We aimed to examine the prevalence of geriatric impairments in older adults with myeloma and the association between geriatric assessment and autologous stem cell transplant eligibility. DESIGN Prospective cohort study. SETTING Two academic medical centers. PARTICIPANTS A total of 40 adults 65 years and older with newly diagnosed myeloma were enrolled. MEASUREMENT Participants completed a primarily self‐administered geriatric assessment, including measures of functional status, comorbidities, polypharmacy, psychosocial status, social support, quality of life, cognition, and physical performance. Outcomes were autologous stem cell transplant eligibility and receipt. RESULTS Forty patients enrolled; their mean age was 71 years. Geriatric impairments were common: 62% reported dependence in one or more instrumental activities of daily living (IADL), 76.9% had polypharmacy (four or more medications), and 47.5% had one or more comorbidities. Median time on the Timed Up and Go was 13.3 ± 4.9 seconds. Those considered candidates for autologous stem cell transplant (N = 26) were younger, with fewer comorbidities, better performance status, and faster performance on the Timed Up and Go test. Factors independently associated with receiving autologous stem cell transplant (N = 21) included age and IADL dependence. CONCLUSION Impairments in geriatric domains are common in this population, even among those considered to have a good performance status. Geriatric assessment domains are associated with both transplant eligibility and receipt. J Am Geriatr Soc 67:987–991, 2019.