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.

Leukocyte telomere length not related to risk of esophageal adenocarcinoma

Cancer Med. 2016 Jul 6. doi: 10.1002/cam4.810. [Epub ahead of print]

Leukocyte telomere length in relation to the risk of Barrett’s esophagus and esophageal adenocarcinoma.

Wennerström EC, Risques RA, Prunkard D, Giffen C, Corley DA, Murray LJ, Whiteman DC, Wu AH, Bernstein L, Ye W, Chow WH, Vaughan TL, Liao LM.

Abstract

Christina Wennerström

Chronic inflammation and oxidative damage caused by obesity, cigarette smoking, and chronic gastroesophageal reflux disease (GERD) are major risk factors associated with Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). EAC has been increasing the past few decades, and early discovery and treatment are crucial for survival. Telomere shortening due to cell division and oxidative damage may reflect the impact of chronic inflammation and could possibly be used as predictor for disease development. We examined the prevalence of shorter leukocyte telomere length (LTL) among individuals with GERD, BE, or EAC using a pooled analysis of studies from the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON). Telomere length was measured in leukocyte DNA samples by Q-PCR. Participants included 1173 patients (386 with GERD, 384 with EAC, 403 with BE) and 736 population-based controls. The association of LTL (in tertiles) along the continuum of disease progression from GERD to BE to EAC was calculated using study-specific odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models adjusted for potential confounders. Shorter LTL were less prevalent among GERD patients (OR 0.57; 95% CI: 0.35-0.93), compared to population-based controls. No statistically significant increased prevalence of short/long LTL among individuals with BE or EAC was observed. In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of EAC. The findings do not suggest a relationship between LTL and BE or EAC.

Greater Hip Circumference Inversely Associated with Risk of Barrett’s

Clin Gastroenterol Hepatol. 2016 Jun 2. pii: S1542-3565(16)30267-1. doi: 10.1016/j.cgh.2016.05.032. [Epub ahead of print]

Inverse Association Between Gluteofemoral Obesity and Risk of Barrett’s Esophagus in a Pooled Analysis.

Kendall BJ, Rubenstein JH, Cook MB, Vaughan TL, Anderson LA, Murray LJ, Shaheen NJ, Corley DA, Chandar AK, Li L, Greer KB, Chak A, El-Serag HB, Whiteman DC, Thrift AP

Abstract

BACKGROUND & AIMS: Gluteofemoral obesity (determined by measurement of subcutaneous fat in the hip and thigh regions) could reduce risks of cardiovascular and

brad_kendall

Brad Kendall

diabetic disorders associated with abdominal obesity. We evaluated whether gluteofemoral obesity also reduces the risk of Barrett’s esophagus (BE), a premalignant lesion associated with abdominal obesity.

METHODS: We collected data from non-Hispanic white participants in 8 studies in the Barrett’s and Esophageal Adenocarcinoma Consortium. We compared measures of hip circumference (as a proxy for gluteofemoral obesity) from cases of BE (n = 1559) separately with 2 control groups: 2557 population-based controls and 2064 individuals with gastroesophageal reflux disease (GERD controls). Study-specific odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using individual participant data and multivariable logistic regression and combined using a random-effects meta-analysis.

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RESULTS: We found an inverse relationship between hip circumference and BE (OR per 5-cm increase, 0.88; 95% CI, 0.81-0.96), compared with population-based controls in a multivariable model that included waist circumference. This association was not observed in models that did not include waist circumference. Similar results were observed in analyses stratified by frequency of GERD symptoms. The inverse association with hip circumference was statistically significant only among men (vs population-based controls: OR, 0.85; 95% CI, 0.76-0.96 for men; OR, 0.93; 95% CI, 0.74-1.16 for women). For men, within each category of waist circumference, a larger hip circumference was associated with a decreased risk of BE. Increasing waist circumference was associated with an increased risk of BE in the mutually adjusted population-based and GERD control models.

CONCLUSIONS: Although abdominal obesity is associated with an increased risk of BE, there is an inverse association between gluteofemoral obesity and BE, particularly among men.

12th BEACON Workshop a Success

Thanks to Doug Corley, Jen Schneider, and Kaiser Permanente Northern California for their efforts and contributions in hosting the 12th Annual BEACON Workshop, and to all participants for making it such a fun and worthwhile meeting.

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