Search

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Supplementary Data - PDF file 117K, Microarray analysis of differentially expressed genes in PHA-533533 resistant cell lines

Supplementary Figures S1-S9 - PDF file 327K, Supplementary Figure S1: A) Baseline expression of CCNE1 and CDK2 in OVCAR-3 (CCNE1 amplified) and OVCAR-4 (CCNE1 gained) cell lines compared to SK-OV-3 (CCNE1 unamplified). *detects both isoforms of CDK2. B) CCNE1 and CDK2 gene expression by RT-PCR after gene knockdown normalized to no siRNA control cells within each cell line. Representative data shown. *detects both isoforms of CDK2. C) Cell viability normalized to no siRNA control cells after transfection with siRNAs against CCNE1 or CDK2. Statistical significance calculated by comparison to non-silencing (NS) siRNA in the same cell line using data from three independent MTS assays performed in triplicate. Average normalized absorbance at 490 nm and SEM plotted (n = 3), T-test *p-value 0.3 for gains and >0.8 for amplifications. Fraction of genome lost (log2 copy number ratio < -0.3) in ovarian tumor samples by B) number of predicted whole genome doublings and C) CCNE1 copy number status. T-test ***p-value < 0.001

Supplementary Methods - PDF file 70K, CDK2 sequencing methods and primer sequences

Supplementary Tables S1-5 - PDF filr 185K, Supplementary Table S1: Essentiality of CDKs in CCNE1 amplified cell lines; Supplementary Table S2: GeneGo gene expression pathways enriched in PHA-533533 resistant cell lines; Supplementary Table S3: Copy number changes identified by SNP microarray in PHA-533533 resistant cell lines; Supplementary Table S4: Gene Set Enrichment Analysis (GSEA) of positional gene sets enriched in amplified or deleted genes specific to PHA-533533 resistant cells; Supplementary Table S5: OVCAR-3 cell line and derivative resistant line karyotypes

PDF file - 150K

PDF file - 119K, Supp Table S1. Regions of differential copy number change between primary tumor samples and most distant abdominal deposit Supp Table S2. Top 50 pathways altered between primary tumors and abdominal deposits Supp Table S3. Individual patient chemotherapy regimens for paired primary and relapse ovarian tumors Supp Table S4. BRCA mutation details for mutation positive cases Supp Table S5. Regions of discrete copy number amplification Supp Table S6. Regions of discrete copy number deletion

Background: Body mass index (BMI) change after a lung cancer diagnosis has been associated with non–small cell lung cancer (NSCLC) survival. This study aimed to quantify the association based on a large-scale observational study. Methods: Included in the study were 7,547 patients with NSCLC with prospectively collected BMI data from Massachusetts General Hospital and Brigham and Women's Hospital/Dana-Farber Cancer Institute. Cox proportional hazards regression with time-dependent covariates was used to estimate effect of time-varying postdiagnosis BMI change rate (% per month) on overall survival (OS), stratified by clinical subgroups. Spline analysis was conducted to quantify the nonlinear association. A Mendelian Randomization (MR) analysis with a total of 3,495 patients further validated the association. Results: There was a J-shape association between postdiagnosis BMI change and OS among patients with NSCLC. Specifically, a moderate BMI decrease [0.5–2.0; HR = 2.45; 95% confidence interval (CI), 2.25–2.67] and large BMI decrease (≥2.0; HR = 4.65; 95% CI, 4.15–5.20) were strongly associated with worse OS, whereas moderate weight gain (0.5–2.0) reduced the risk for mortality (HR = 0.78; 95% CI, 0.68–0.89) and large weight gain (≥2.0) slightly increased the risk of mortality without reaching statistical significance (HR = 1.10; 95% CI, 0.86–1.42). MR analyses supported the potential causal roles of postdiagnosis BMI change in survival. Conclusions: This study indicates that BMI change after diagnosis was associated with mortality risk. Impact: Our findings, which reinforce the importance of postdiagnosis BMI surveillance, suggest that weight loss or large weight gain may be unwarranted.

Background We examined whether body mass index (BMI) changes in adulthood, prior to disease onset, are associated with overall survival among esophageal adenocarcinoma patients. Methods We included 285 histologically confirmed patients with a complete baseline BMI questionnaire. Using extended Cox regression models, we obtained adjusted hazard ratios (HRs) for the associations between overall survival and BMI at diagnosis, BMI 6 months before diagnosis, self‐reported average adult BMI, and ΔBMI (BMI 6 months before diagnosis minus average adult BMI), categorized into tertiles 25 and, Body mass index (BMI) gain in adulthood before cancer onset is associated with poor overall survival among esophageal adenocarcinoma patients, independent of BMI at diagnosis. Despite some reports that higher BMI may be protective for survival, we found no survival benefit of adding body weight prior to diagnosis, and suspect previous findings are driven by reverse causation.

textabstractObjective: To investigate the association of migraine genetic variants with cerebral blood flow (CBF). Background: Migraine is a common disorder with many genetic and non-genetic factors affecting its occurrence. The exact pathophysiological mechanisms underlying the disease remain unclear, but are known to involve hemodynamic and vascular disruptions. Recent genome-wide association studies have identified 44 genetic variants in 38 genetic loci that affect the risk of migraine, which provide the opportunity to further disentangle these mechanisms. Methods: We included 4665 participants of the population-based Rotterdam Study (mean age 65.0 ± 10.9 years, 55.6% women). Cross-sectional area (mm2), flow velocity (mm/s), and blood flow (mL/min) were measured in both carotids and the basilar artery using 2-dimensional phase-contrast magnetic resonance imaging. We analyzed 43 previously identified migraine variants separately and calculated a genetic risk score (GRS). To assess the association with CBF, we used linear regression models adjusted for age, sex, and total brain volume. Hierarchical clustering was performed based on the associations with CBF measures and tissue enrichment. Results: The rs67338227 risk allele was associated with higher flow velocity and smaller cross-sectional area in the carotids (Pminimum = 3.7 × 10−8). Other variants were related to CBF with opposite directions of effect, but not significantly after multiple testing adjustments (P

Background: Higher levels of circulating 25-hydroxyvitamin D [25(OH)D] are associated with longer survival in several cancers, but the results have differed across cancer sites. The association between serum 25(OH)D levels and overall survival (OS) time in esophageal adenocarcinoma remains unclear. Methods: We utilized serum samples from 476 patients with primary esophageal adenocarcinoma, recruited from Massachusetts General Hospital (Boston, MA) between 1999 and 2015. We used log-rank tests to test the difference in survival curves across quartiles of 25(OH)D levels and extended Cox modeling to estimate adjusted HRs. We tested for interactions between clinical stage or BMI on the association between 25(OH)D and OS. We additionally performed sensitivity analyses to determine whether race or timing of blood draw (relative to treatment) affected these results. Results: We found no evidence that survival differed across quartiles of 25(OH)D (log rank P = 0.48). Adjusting for confounders, we found no evidence that the hazard of death among the highest quartile of 25(OH)D (quartile 1) differed from any other quartile [quartile 2 HR = 0.90, 95% confidence interval (CI), 0.67–1.23; quartile 3 HR = 1.03, 95% CI, 0.76–1.38; quartile 4 (lowest) HR = 0.98, 95% CI, 0.72–1.33]. Sensitivity analyses yielded consistent results when accounting for race or time between diagnosis and blood draw. Moreover, we did not find evidence of interaction between 25(OH)D and clinical stage or BMI on OS. Conclusions: Serum level of 25(OH)D near time of diagnosis was not associated with OS in patients with esophageal adenocarcinoma. Impact: Screening 25(OH)D levels among patients with esophageal adenocarcinoma at diagnosis is not clinically relevant to their cancer prognosis based on present evidence.

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association ( GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms ( SNPs) significantly associated with migraine risk ( P

Aim: We studied body composition throughout the first year after diagnosis and its association with overall survival (OS) among esophageal cancer patients. Methods: We utilized clinical abdominal computerized tomography (CT) scans from esophageal adenocarcinoma (EA) and squamous cell carcinoma (SCC) patients, who were diagnosed between 1999 and 2018 and enrolled in an ongoing study at Massachusetts General Hospital. A deep learning based automated segmentation of each CT at the L3 slice to obtain muscle (MA), subcutaneous adiposity tissue (SAT), and visceral adiposity tissue (VAT). These measures were normalized by age-, sex-, and race using a published cohort of non-cancer patient CT body composition database. We defined baseline sarcopenia using the Martin et. al. 2013 cut points. Among available scans, we obtained HRs for body composition metrics throughout the first year after diagnosis (3-6 months, 6-9 months, 9-12 months) using conditional follow-up and time-varying metrics. We obtained OS hazard ratios (HR) for pre-treatment baseline metrics using an extended cox proportional hazard model. Multivariable models included smoking status, histology, chemotherapy, radiation, and time-dependent surgery as covariates, and baseline hazards were stratified by lymph node status at diagnosis (lymph node negative, lymph node positive, and metastatic). We performed additional sensitivity baseline analyses restricting to EA patients, patients who received trimodality therapy, and stratified by lymph node status. Results: 251 patients (80.9% EA) had pre-treatment CT scans, and 438 patients (85.4% EA) had at least one CT scan throughout the first year after diagnosis. In the complete cohort, normalized baseline body composition measures and sarcopenia were not associated with OS in the univariable or multivariable analyses. Among EA only, baseline MA was associated with longer survival (HR: 0.85 per standard deviation increase; 95% CI 0.73-0.99; p=0.04). 3-6 months after diagnosis (N=206 patients), higher normalized MA, SAT, and VAT were all significantly associated (p6 months after diagnosis. The strongest association was 9-12 months after diagnosis (N=131), where a standard deviation increase in MA was associated with 0.56 hazard of death (95%CI 0.42-0.75; p Conclusions: Muscle area in the first year after diagnosis is strongly associated with survival in esophageal cancer. Since associations were strongest during and after treatment, directionality of this association is uncertain, and we will investigate additional factors to determine the clinical utility of these associations. Citation Format: Elizabeth Loehrer, Jakob Weiss, Raymond H. Mak, Junwei Lu, Andrea Shafer, Michael H. Rosenthal, Hugo J. Aerts, David C. Christiani. Body composition and overall survival in esophageal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 761.

CKD is linked with various brain disorders. Whereas brain integrity is dependent on cerebral perfusion, the association between kidney function and cerebral blood flow has yet to be determined. This study was performed in the framework of the population-based Rotterdam Study and included 2645 participants with mean age of 56.6 years (45% men). We used eGFR and albumin-to-creatinine ratio to assess kidney function and performed phase-contrast magnetic resonance imaging of basilar and carotid arteries to measure cerebral blood flow. Participants had an average (SD) eGFR of 86.3 (13.4) ml/min per 1.73 m(2) and a median (interquartile range) albumin-to-creatinine ratio of 3.4 (2.2-6.1) mg/g. In age- and sex-adjusted models, a higher albumin-to-creatinine ratio was associated with lower cerebral blood flow level (difference in cerebral blood flow [milliliters per minute per 100 ml] per doubling of the albumin-to-creatinine ratio, -0.31; 95% confidence interval, -0.58 to -0.03). The association was not present after adjustment for cardiovascular risk factors (P=0.10). Each 1 SD lower eGFR was associated with 0.42 ml/min per 100 ml lower cerebral blood flow (95% confidence interval, 0.01 to 0.83) adjusted for cardiovascular risk factors. Thus, in this population-based study, we observed that lower eGFR is independently associated with lower cerebral blood flow.

The question remains whether reduced cerebral blood flow (CBF) leads to brain atrophy or vice versa. We studied the longitudinal relation between CBF and brain volume in a community-dwelling population. In the Rotterdam Study, 3011 participants (mean age 59.6 years (s.d. 8.0)) underwent repeat brain magnetic resonance imaging to quantify brain volume and CBF at two time points. Adjusted linear regression models were used to investigate the bidirectional relation between CBF and brain volume. We found that smaller brain volume at baseline was associated with a steeper decrease in CBF in the whole population (standardized change per s.d. increase of total brain volume (TBV) = 0.296 (95% confidence interval (CI) 0.200; 0.393)). Only in persons aged ≥ 65 years, a lower CBF at baseline was associated with steeper decline of TBV (standardized change per s.d. increase of CBF = 0.003 (95% CI −0.004; 0.010) in the whole population and 0.020 (95% CI 0.004; 0.036) in those aged ≥65 years of age). Our results indicate that brain atrophy causes CBF to decrease over time, rather than vice versa. Only in persons aged >65 years of age did we find lower CBF to also relate to brain atrophy.

Introduction Observations that migraine increases risk of cardiovascular disease and ischemic brain changes may suggest sustained vascular differences between migraineurs and controls. In a population-based setting, we compared cerebral blood flow between migraineurs in the attack-free period and controls. Methods Between 2006 and 2008, 2642 participants, aged 45–65, from the Rotterdam Study completed a migraine questionnaire and had complete usable MRI data. Participants were classified into controls (N = 2033), probable migraine (N = 153), or migraine (N = 456). Using 2D phase contrast MRI, we performed a cross-sectional analysis of the effect of migraine on total cerebral blood flow (tCBF), parenchymal cerebral blood flow (pCBF), and blood flow in each intracranial arterial using linear regression. Additionally, we performed stratified analysis of subtypes of migraine. Results Compared with controls, migraineurs had higher pCBF (1.07 ml/min/100 ml, 95% CI 0.08; 2.05). In particular, migraineurs had significantly higher blood flow in the basilar artery (4.70 ml/min, 95% CI 0.77; 8.62). Discussion Migraineurs in the attack-free period have higher pCBF, particularly basilar artery flow, compared to controls, supporting the notion of sustained vascular differences between these groups outside of migraine attacks.

Purpose: Amplification of cyclin E1 (CCNE1) is associated with poor outcome in breast, lung, and other solid cancers, and is the most prominent structural variant associated with primary treatment failure in high-grade serous ovarian cancer (HGSC). We have previously shown that CCNE1-amplified tumors show amplicon-dependent sensitivity to CCNE1 suppression. Here, we explore targeting CDK2 as a novel therapeutic strategy in CCNE1-amplified cancers and mechanisms of resistance. Experimental Design: We examined the effect of CDK2 suppression using RNA interference and small-molecule inhibitors in SK-OV-3, OVCAR-4, and OVCAR-3 ovarian cancer cell lines. To identify mechanisms of resistance, we derived multiple, independent resistant sublines of OVCAR-3 to CDK2 inhibitors. Resistant cells were extensively characterized by gene expression and copy number analysis, fluorescence-activated cell sorting profiling and conventional karyotyping. In addition, we explored the relationship between CCNE1 amplification and polyploidy using data from primary tumors. Results: We validate CDK2 as a therapeutic target in CCNE1-amplified cells by showing selective sensitivity to suppression, either by gene knockdown or using small-molecule inhibitors. In addition, we identified two resistance mechanisms, one involving upregulation of CDK2 and another novel mechanism involving selection of polyploid cells from the pretreatment tumor population. Our analysis of genomic data shows that polyploidy is a feature of cancer genomes with CCNE1 amplification. Conclusions: These findings suggest that cyclinE1/CDK2 is an important therapeutic target in HGSC, but that resistance to CDK2 inhibitors may emerge due to upregulation of CDK2 target protein and through preexisting cellular polyploidy. Clin Cancer Res; 19(21); 5960–71. ©2013 AACR.

High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients. Cancer Res; 72(16); 4060–73. ©2012 AACR.

We investigated the potential prognostic association between vitamin D levels (25-Hydroxyvitamin D [25(OH)D]) and vitamin D pathway single nucleotide polymorphisms (SNPs) with overall survival (OS) in esophageal adenocarcinoma (EA) patients. EA patients were recruited from Massachusetts General Hospital near the time of their diagnosis between 1999 and 2016. At the time of recruitment, patients completed a baseline questionnaire and provided blood and serum samples. Serum 25(OH)D levels were measured using radioimmunoassay and adjusted for month of blood draw. Genotypes for 48 tag SNPs from seven candidate genes in the vitamin D pathway (GC, CYP2R1, CYP27A1, CYP27B1, CYP24A1, VDR and RXRA) were determined from whole blood DNA. For survival outcomes, we used log-rank test and a multivariable extended Cox model to estimate adjusted hazard ratio (HR) of death. HR models for each SNP were restricted to patients who identified as White and adjusted for age, sex, smoking status, diagnosis year, and treatment, stratifying baseline hazard by clinical stage and modeling surgical resection as a time-dependent covariate. HR models by quartiles 25(OH)D, additionally adjusted for body mass index (BMI), and timing of blood draw. Our analyses included EA patients with complete information on relevant confounders and predictors of OS. The 25(OH)D analysis included 463 EA patients and 337 deaths, with median follow-up of 23.1 months. The mean 25(OH)D level at diagnosis was 20.7 ng/mL. We found no evidence that OS curves differed across quartiles of vitamin D (log rank p=0.83). In the adjusted extended cox model, we found no difference in OS among the highest quartile and quartiles 2-4 (respectively, HR (95% confidence interval), 0.95 (0.70, 1.31), 1.03 (0.76,1.39), 1.01 (0.73, 1.38), global p=0.97). We did not find evidence of interaction between 25(OH)D and clinical stage (p=0.88) or BMI (p=0.43) on OS, and this relationship did not differ by timing of blood draw. Preliminary SNP analysis included 424 EA patients and 305 deaths, with median follow-up of 24.1 months. Two SNPs in CYP24A1 (SNP, HR (95% confidence interval) per minor allele: rs1570669, 1.23 (1.04-1.45); rs927650, 1.22 (1.04-1.44)), two SNPs in GC (rs4588, 1.25(1.04-1.49); rs7041, 0.84(0.71-0.99)), and one SNP in RXRA (rs7039190, 1.57(1.06, 2.31)) were marginally associated with OS in the multivariable survival model. SNPs were not statistically significant after adjusting p-value for multiple testing. Based on the available evidence from our analyses, markers in the vitamin D pathway at the time of diagnosis are not clinically relevant markers of EA survival. Citation Format: Elizabeth Loehrer, Rebecca Betensky, Ruyang Zhang, Li Su, Edward Giovannucci, David Christiani. Molecular markers of the vitamin D pathway and esophageal adenocarcinoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 247.

Background B-cell translocation gene 2 (BTG2), which functions as a tumor suppress gene, has been reported to be involved in several cancers. However, no study has focused on its role in lung cancer progression or prognosis. We aimed to investigate the role of BTG2 in early-stage non-small cell lung cancer (NSCLC) survival. Patients and methods This study included 1,230 early-stage (1-2) surgically treated NSCLC patients with methylation and expression data from five international cohorts. We built a prognostic model based on methylation. Then, we explored BTG2 expression and NSCLC survival in 3,038 cases, including the above-mentioned cohorts as well as 17 extended public datasets by meta-analysis. Further, we integrated the clinical information, expression, and methylation to build an integration model and evaluated its prediction ability for 5-year survival. Results Three risk CpG probes (cg01798157, cg06373167, cg23371584) were associated with overall survival. The prognostic model could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51 to 2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 acted as a tumor-suppress gene in each cohort (HR range, 0.28 to 0.68). A meta-analysis showed high BTG2 expression was associated with better survival (HR = 0.61, 95%CI: 0.54-0.68). The three CpG probes were all negatively correlated with BTG2 expression. Additionally, the integration model showed a better prediction ability in the training set [area under the curve (AUC) = 0.78] and the validation set (AUC = 0.77). The integrated signature showed a better predictive ability among cases with adjuvant therapy (AUC = 0.85). In addition, 17 miRNAs including miR-21 and miR-23a were associated with BTG2 expression and survival. Conclusions: methylation and integrated prognostic signatures of BTG2 are stable and reliable biomarkers for early-stage NSCLC. These markers may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future. Citation Format: Sipeng Shen, Li Su, Ruyang Zhang, Elizabeth Loehrer, Michael Lanuti, Nancy Diao, David Christiani. A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-159.

Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 x 10-8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Purpose: Though BMI is a known risk factor for esophageal adenocarcinoma (EA), the effect of BMI on EA overall survival remains unclear. Procedures: The source population is the Esophageal Cancer Study, an ongoing case-control and survivorship study of esophageal cancer patients recruited from Massachusets General Hospital and Dana-Farber Cancer Institute. In September of 2004, the study introduced a new patient questionnaire that included questions on weight throughout adulthood. For this study, we restricted our analysis to Caucasian, male patients with histologically confirmed EA who received their initial diagnosis between 9/1/2004 and 12/31/2014, and who were older than age 40 at time of diagnosis (281 patients). Our exposures of interests were BMI categories (30) and ΔBMI (the average BMI past the age of 40 minus BMI at time of diagnosis), categorized the differences into 2 (people who lost substantial weight). We used an extended Cox proportional hazards model to obtain hazard ratios (HR) of BMI at diagnosis and ΔBMI, stratifying baseline hazard by cancer stage, having surgery as a time dependent covariate, and adjusting for radiation and chemotherapy treatment, age, sustained inability to eat solid foods after diagnosis, and smoking status. Results: Of the 282 patients that met our eligibility criteria, 211 men with complete information available were included in the analyses, and there were 131 recorded events during follow-up. In this study population, mean age at diagnosis was 63.7 years (SD±9.8), median survival was 2.6 years, mean average BMI after 40 years of age was 29.0 kg/m2(SD±4.5), and mean BMI at diagnosis was 27.4 kg/m2(SD±4.4). Compared to obese subjects at diagnosis, underweight, healthy weight, and overweight at diagnosis respectively had an adjusted hazard ratios of death (HR) of 2.72(95% CI: 0.59-12.45), 1.79 (95%, CI: 1.06-3.02) and 1.08 (95% CI: 0.65-1.74) (BMI category p=0.04), likely demonstrating reverse causation. Adjusting for confounders, the ΔBMI model shows that patients who lost substantial weight by diagnosis had the highest hazard of death, compared to patients who gained weight in late life prior to diagnosis (HR=0.70, 95% CI: 0.45-1.1) and patients who lost some weight (HR=0.55, 95% CI: 0.35-0.9)( ΔBMI category p=0.05). The strong effect of ΔBMI even after adjusting for patients’ inability or lack of desire to eat (anorexia), implicates cachexia as a possible independent mechanism of this association. In addition, age at dx, stage at diagnosis, and surgical resection were significant predictors of overall survival. Conclusion: Substantial change in BMI prior to diagnosis indicates poor overall survival in middle-aged and elderly Caucasian men with esophageal adenocarcinoma. Citation Format: Elizabeth A. Loehrer, David Christiani. BMI and esophageal adenocarcinoma survival [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 5322. doi:10.1158/1538-7445.AM2017-5322

Cerebral microbleeds are considered an imaging marker of cerebral small vessel disease. The location of microbleeds is thought to reflect the underlying pathology. Microbleeds in the deep and infratentorial region are thought to reflect hypertensive arteriopathy whereas lobar microbleeds are associated clinically with cerebral amyloid angiopathy (CAA). Aside from patient populations, microbleeds are frequently observed in seemingly asymptomatic populations. Moreover, many elderly, both in clinical and preclinical populations, have multiple coexisting pathologies in their brains, which complicates the interpretation of cerebral microbleeds, especially early in the clinical course. In this commentary, we discuss the influence of the strongest genetic risk factor for CAA, Apolipoprotein E (APOE), in the spatial distribution of microbleeds, and we additionally address issues in interpretation and implication of the location of microbleeds in clinical and asymptomatic populations.

In cerebral amyloid angiopathy patients, microbleeds often cluster, mostly occipital, and are associated with apolipoprotein E (APOE) genotype. Microbleeds also frequently occur in the asymptomatic, general population. In this population, we investigated spatial distribution of microbleeds and whether this is influenced by APOE genotype. In 292 persons with microbleeds, we labeled microbleeds on baseline and follow-up magnetic resonance images. We calculated distance between incident and prevalent microbleeds within and between persons and performed lobar segmentation on the magnetic resonance images. Subsequently, we investigated proximity and lobar distribution in strata of APOE genotype. Microbleeds occurred closer within persons than between persons (-42.2 mm, 95% confidence interval, -44.6 to -39.9; p < 0.001). Microbleeds within APOE epsilon 2 and epsilon 4 carriers occurred closer than those in persons with epsilon 3 epsilon 3 genotype (-11.9 mm, 95% confidence interval, -24.4 to 0.6; p = 0.06). Persons with epsilon 2 and epsilon 4 alleles had a larger proportion of microbleeds in the occipital lobe than persons with epsilon 3 epsilon 3 genotype. Similar to cerebral amyloid angiopathy patients, microbleeds in the general population cluster and the distribution is affected by APOE genotype. (C) 2014 Elsevier Inc. All rights reserved.

Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 44 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

INTRODUCTION: This retrospective study aimed to characterize the clinical hematological and immunological features of patients with thymic epithelial neoplasms.METHODS: From a cohort of 512 patients with thymic epithelial neoplasms, 79 patients diagnosed with autoimmune/immunodeficiency conditions or signs and/or symptoms suggesting an autoimmune or immunodeficiency state were evaluated by standard immunological and hematological testing.RESULTS: Elevated percentages of CD2+, CD3+, and CD8+ lymphocytes were observed in 44 (57.1%), 33 (41.8%), and 32 (40.5%) patients. Low CD4+ and CD19+ percentages were observed in 25 (31.6%) and 36 (46.2%), respectively; CD4+:CD8+ ratios were inverted in 18 (22.8%). IgG, IgA, and IgM levels were low in 12 (15.8%), 9 (11.7%) and 15 (19.7%) patients, respectively. Patients with immunodeficiency condition(s) were more likely to have high CD8+ percentages (p = 0.040), low CD19+ percentages (p = 0.025), and/or inverted CD4+/CD8+ ratios (p = 0.034). Patients with autoimmune condition(s) were more likely to have a high/normal CD4+ percentage (p = 0.038). High CD2+ percentages were associated with lower mean IgG and IgA levels (p = 0.030 and p = 0.017, respectively). High CD3+ and CD8+ percentages were associated with lower mean IgA levels (p = 0.046 and p = 0.013, respectively). Low CD19+ percentages were associated with lower mean IgG and IgA levels (p = 0.004 and p CONCLUSION: Signs/symptoms and history of autoimmune and immunodeficiency conditions among patients with thymic epithelial neoplasms are associated with high frequencies of abnormalities in immunoglobulin levels and lymphocyte immunophenotypes, suggesting a role for their assessment.