Anderson, Lesley A

Abstract Background: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set–based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set–based genetic association approach. Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set–based genetic association approach as an alternative method for TWAS analysis.

Abstract Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

AbstractDespite the identification of acquired genetic mutations associated with Myeloproliferative Neoplasms (MPNs) there is a paucity of information relating to modifiable risk factors that may lead to these mutations. The MOSAICC Study was an exploratory case‐control study of polycythemia vera (PV), essential thrombocythemia (ET), and Myelofibrosis (MF). MPN patients and population controls (identified by General Practitioners) and non‐blood relative/friend controls were recruited from 2 large UK centers. Participants completed a telephone‐based questionnaire analyzed by unconditional logistic regression analysis adjusting for potential confounders. Risk factors for MPNs identified included increasing childhood household density [odds ratio (OR) 2.55, 95% confidence interval (CI) 1.16–5.62], low childhood socioeconomic status (OR 2.30, 95%CI 1.02–5.18) and high pack years smoking (OR 2.19, 95%CI 1.03–4.66) and current smoking restricted to JAK2 positive PV cases (OR 3.73, 95%CI 1.06–13.15). Obesity was linked with ET (OR 2.59, 95%CI 1.02–6.58) confirming results in previous cohort studies. Receipt of multiple CT scans was associated with a strongly increased risk of MPN although with wide confidence intervals (OR 5.38, 95%CI 1.67–17.3). Alcohol intake was inversely associated with risk of PV (OR 0.41, 95%CI 0.19–0.92) and ET (OR 0.48, 95%CI 0.24–0.98). The associations with childhood household density, high pack years smoking and alcohol were also seen in multivariate analysis. This is the largest case control study in MPNs to date and confirms the previously reported associations with obesity and cigarette smoking from cohort studies in addition to novel associations. In particular, the role of smoking and JAK2 mutation cases merits further evaluation.

Abstract Introduction The Classic Myeloproliferative Neoplasms (MPNs), characterised by an over production of one or more cells of the myeloid lineage, are classified into polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF). Despite the identification of numerous genetic mutations, a paucity of information relating to medical and lifestyle factors contributing to the aetiology of these diseases remains. Methods The MOSAICC Study was an exploratory case-control study of MPNs. MPN patients were recruited between two sites, Belfast and Southampton, in preparation for a planned UK-wide investigation. Population controls (identified by General Practitioners) and non-blood relative/friend controls were also recruited. Participants completed a telephone-based questionnaire seeking information on a range of medical, environmental, lifestyle and occupational risk factors. Risk factors were assessed using unconditional logistic regression with adjustment for potential confounders. Results Risk factors identified included smoking [≥25 pack years vs. never: odds ratio (OR) 3.14, 95% confidence interval (CI) 1.26-7.87], increasing childhood household density [>2 vs <1 Child(ren)/room: OR 3.29, 95% CI 1.31-8.30], history of heart disease (OR 3.31, 95% CI 1.23-8.87), CT scans (≥3 vs. none: OR 4.92, 95% CI 1.55-15.67), having an implant (OR 10.77, 95% CI 1.01-3.10), and pig ownership (OR 5.92, 95% CI 1.17-29.92). Alcohol was associated with a reduced risk of MPNs (OR 0.49, 95% CI 0.28-0.88) as was home working on car exhausts (OR 0.33, 95% CI 0.12-0.88), painting at home (OR 0.49, 95% CI 0.28-0.86) and short haul air travel (p for trend 0.012). Participants working in occupations with high exposure to environmental tobacco smoke had an excess risk of MPN (OR 2.45, 95% CI 1.12-5.37). Work-based radiation and solvent exposure also appeared to increase risk of MPNs (p<0.05). Conclusions This exploratory study has confirmed a reported association between cigarette smoking and MPNs. It has identified some potential novel risk factors including work-based radiation and solvent exposure. The findings of this study need to be replicated in a larger, adequately powered, study in order to identify important risk factors for the classic MPNs. Conflict of Interest The authors declare no conflict of interest. Acknowledgments: The MOSAICC Study team acknowledges the support of the National Institute for Health Research, through the Northern Ireland Cancer Research Network (NICRN) and for Southampton the Central South Coast Cancer Network (CSCCN). The team thank those who have participated in the MOSAICC study and the personnel who assisted in the recruitment of patients. Disclosures Mesa: CTI Biopharma: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; Pfizer: Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; Gilead: Research Funding.

The myeloproliferative neoplasms (MPN) including polycythaemia vera (PV), essential thrombocythaemia and primary myelofibrosis (PMF) are rare diseases contributing to significant morbidity. Symptom management is a prime treatment objective but current symptom assessment tools have not been validated compared to the general population. The MPN‐symptom assessment form (MPN‐SAF), a reliable and validated clinical tool to assess MPN symptom burden, was administered to MPN patients (n = 106) and, for the first time, population controls (n = 124) as part of a UK case–control study. Mean symptom scores were compared between patients and controls adjusting for potential confounders. Mean patient scores were compared to data collected by the Mayo Clinic, USA on 1,446 international MPN patients to determine patient group representativeness. MPN patients had significantly higher mean scores than controls for 25 of the 26 symptoms measured (P < 0.05); fatigue was the most common symptom (92.4% and 78.1%, respectively). Female MPN patients suffered worse symptom burden than male patients (P < 0.001) and substantially worse burden than female controls (P < 0.001). Compared to the Mayo clinic patients, MPN‐UK patients reported similar symptom burden but lower satiety (P = 0.046). Patients with PMF reported the worst symptom burden (88.3%); significantly higher than PV patients (P < 0.001). For the first time we report quality of life was worse in MPN‐UK patients compared with controls (P < 0.001). Am. J. Hematol. 90:864–870, 2015. © 2015 Wiley Periodicals, Inc.

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases including polycythemia vera (PV), essential thrombocythemia (ET), and primary(idiopathic) myelofibrosis (PMF). In this systematic review, we provide a comprehensive report on the incidence and prevalence of MPNs across the globe. Electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) were searched from their inception to August 2012 for articles reporting MPN incidence or prevalence rates. A random effects meta‐analysis was undertaken to produce combined incidence rates for PV, ET, and PMF. Both heterogeneity and small study bias were assessed. Thirty‐four studies were included. Reported annual incidence rates ranged from 0.01 to 2.61, 0.21 to 2.27, and 0.22 to 0.99 per 100,000 for PV, ET, and PMF, respectively. The combined annual incidence rates for PV, ET, and PMF were 0.84, 1.03, and 0.47 per 100,000. There was high heterogeneity across disease entities (I2 97.1–99.8%) and evidence of publication bias for ET and PMF (Egger test, P = 0.007 and P ≤ 0.001, respectively).The pooled incidence reflects the rarity of MPNs. The calculated pooled incidence rates do not reflect MPN incidence across the globe due to the high unexplained heterogeneity. Improved, widespread registration of MPNs would provide better information for global comparison of the incidence and prevalence of MPNs. Am. J. Hematol. 89:581–587, 2014. © 2014 Wiley Periodicals, Inc.