Genetic and non-genetic predictors of esophageal adenocarcinoma

Gastroenterology. 2018 Apr;154(5):1273-1281.e3. doi: 10.1053/j.gastro.2017.12.003. Epub 2017 Dec 13.

Determining Risk of Barrett’s Esophagus and Esophageal Adenocarcinoma Based on Epidemiologic Factors and Genetic Variants.

Dong J, Buas MF, Gharahkhani P, Kendall BJ, Onstad L, Zhao S, Anderson LA, Wu AH, Ye W, Bird NC, Bernstein L, Chow WH, Gammon MD, Liu G, Caldas C, Pharoah PD, Risch HA, Iyer PG, Reid JB, Lardie LJ, Lagergren J, Shaneen NJ, Corley DA, Fitzgerald RC, Whiteman DC, Vaughan TL, Thrift AP.

Abstract

BACKGROUND & AIMS: We developed comprehensive models to determine risk of Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors.

Aaron Thrift

METHODS: We used pooled data from 3288 patients with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett’s and EAC consortium as well as the United Kingdom’s BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis.

RESULTS: Individuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89-2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07-2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%.

CONCLUSIONS: We used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use.

 

NSAIDs use not related to risk of Barrett’s

Am J Gastroenterol. 2016 Nov;111(11):1528-1535. doi: 10.1038/ajg.2016.348. Epub 2016 Aug 30.

Nonsteroidal Anti-Inflammatory Drug Use is Not Associated With Reduced Risk of Barrett’s Esophagus.

Thrift AP1,2, Anderson LA3, Murray LJ3, Cook MB4, Shaheen NJ5, Rubenstein JH6,7, El-Serag HB1,8, Vaughan TL9, Schneider JL10, Whiteman DC11, Corley DA10.

Abstract

OBJECTIVES:

Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of esophageal adenocarcinoma. Epidemiological studies examining the association between NSAID use and the risk of the precursor lesion, Barrett’s esophagus, have been inconclusive.

METHODS:

We analyzed pooled individual-level participant data from six case-control studies of Barrett’s esophagus in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON). We compared medication use from 1,474 patients with Barrett’s esophagus separately with two control groups: 2,256 population-based controls and 2,018 gastroesophageal reflux disease (GERD) controls. Study-specific odds ratio (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression models and were combined using a random-effects meta-analytic model.

RESULTS:

Regular (at least once weekly) use of any NSAIDs was not associated with the risk of Barrett’s esophagus (vs. population-based controls, adjusted OR=1.00, 95% CI=0.76-1.32, I2=61%; vs. GERD controls, adjusted OR=0.99, 95% CI=0.82-1.19, I2=19%). Similar null findings were observed among individuals who took aspirin or non-aspirin NSAIDs. We also found no association with highest levels of frequency (at least daily use) and duration (?5 years) of NSAID use. There was evidence of moderate between-study heterogeneity; however, associations with NSAID use remained non-significant in “leave-one-out” sensitivity analyses.

CONCLUSIONS:

Use of NSAIDs was not associated with the risk of Barrett’s esophagus. The previously reported inverse association between NSAID use and esophageal adenocarcinoma may be through reducing the risk of neoplastic progression in patients with Barrett’s esophagus.

New method for GxE analyses identifies 2 new Barrett’s SNPs

Am J Hum Genet. 2016 Aug 4;99(2):352-65. doi: 10.1016/j.ajhg.2016.06.018.

Constrained Score Statistics Identify Genetic Variants Interacting with Multiple Risk Factors in Barrett’s Esophagus.

Dai JY, Tapsoba Jde D, Buas MF; BEACON Consortium, Risch HA, Vaughan TL

Abstract

Few gene-environment interactions (G × E) have been discovered in cancer epidemiology thus far, in part due to the large number of possible G × E to be investigated and inherent low statistical power of traditional analytic methods for discovering G × E. We consider simultaneously testing for interactions between several related exposures and a genetic variant in a genome-wide study. To improve power, constrained testing strategies are proposed for multivariate gene-environment interactions at two levels: interactions that have the same direction (one-sided or bidirectional hypotheses) or are proportional to respective exposure main effects (a variant of Tukey’s one-degree test). Score statistics were developed to expedite the genome-wide computation. We conducted extensive simulations to evaluate validity and power performance of the proposed statistics, applied them to the genetic and environmental exposure data for esophageal adenocarcinoma and Barrett’s esophagus from the Barretts Esophagus and Esophageal Adenocarcinoma Consortium (BEACON), and discovered three loci simultaneously interacting with gastresophageal reflux, obesity, and tobacco smoking with genome-wide significance. These findings deepen understanding of the genetic and environmental architecture of Barrett’s esophagus and esophageal adenocarcinoma.

Large-scale meta-analysis identifies nine additional susceptibility loci

Lancet Oncol. 2016 Oct;17(10):1363-1373. doi: 10.1016/S1470-2045(16)30240-6. Epub 2016 Aug 12.

Genome-wide association studies in oesophageal adenocarcinoma and Barrett’s oesophagus: a large-scale meta-analysis.

Gharahkhani P, Fitzgerald RC, Vaughan TL, et al.

Abstract

BACKGROUND:

Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett’s oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett’s oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett’s oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett’s oesophagus and oesophageal adenocarcinoma.

METHODS:

We did a meta-analysis of all genome-wide association studies of Barrett’s oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5?×?10-8). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms.

FINDINGS:

Our sample comprised 6167 patients with Barrett’s oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17?159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett’s oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8?×?10-10), MSRA (rs17749155; p=5·2?×?10-10), LINC00208 and BLK (rs10108511; p=2·1?×?10-9), KHDRBS2 (rs62423175; p=3·0?×?10-9), TPPP and CEP72 (rs9918259; p=3·2?×?10-9), TMOD1 (rs7852462; p=1·5?×?10-8), SATB2 (rs139606545; p=2·0?×?10-8), and HTR3C and ABCC5 (rs9823696; p=1·6?×?10-8). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6?×?10-8) and was independent of Barrett’s oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10-6) belonged to muscle cell differentiation and to mesenchyme development and differentiation.

INTERPRETATION:

Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett’s oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett’s oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett’s oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies.

BEACON activity update

  • The publications page has been update with 10 (!) new BEACON publications. Two others have been submitted.
  • We are no longer using BaseCamp for managing BEACON resources due to cost contraints. All study questionnaires and other documents that were on BaseCamp are being kept on an encrypted website and available to members by request.

Variants in COX pathway linked to risk of Barrett’s esophagus

Gut. 2016 Aug 2. pii: gutjnl-2016-311622. doi: 10.1136/gutjnl-2016-311622. [Epub ahead of print]

Germline variation in inflammation-related pathways and risk of Barrett’s oesophagus and oesophageal adenocarcinoma.

Buas MF, He Q, Johnson LG, Onstad L, Levine DM, Thrift AP, Gharahkhani P, Palles C, Lagergren J, Fitzgerald RC, Ye W, Caldas C, Bird NC, Shaheen NJ, Bernstein L, Gammon MD, Wu AH, Hardie LJ, Pharoah PD, Liu G, Iyer P, Corley DA, Risch HA, Chow WH, Prenen H, Chegwidden L, Love S, Attwood S, Moayyedi P, MacDonald D, Harrison R, Watson P, Barr H, deCaestecker J, Tomlinson I, Jankowski J, Whiteman DC, MacGregor S, Vaughan TL, Madeleine MM.

Abstract

OBJECTIVE:

snip_20160818114616

Matt Buas

Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett’s oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA.

DESIGN:

We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-?B. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk.snip_20160818113746

RESULTS:

We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10-5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk.

CONCLUSIONS:

This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.