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.
Chang ET, Liu Z, Hildesheim A, Liu Q, Cai Y, Zhang Z, Chen G, Xie SH, Cao SM, Shao JY, Jia WH, Zheng Y, Liao J, Chen Y, Lin L, Ernberg I, Vaughan TL, Adami HO, Huang G, Zeng Y, Zeng YX, Ye W.
The magnitude and patterns of associations between smoking and risk of nasopharyngeal carcinoma (NPC) in high-incidence regions remain uncertain. Associations with active and passive tobacco smoking were estimated using multivariate logistic regression in a population-based case-control study of 2,530 NPC cases and 2,595 controls in Guangdong and Guangxi, southern China, in 2010-2014. Among men, risk of NPC was significantly higher in current smokers compared with never smokers (odds ratio (OR) = 1.32, 95% confidence interval (CI): 1.14, 1.53) but not in former smokers (OR = 0.92, 95% CI: 0.73, 1.17). Risk increased with smoking intensity (per 10 cigarettes/day, OR = 1.09, 95% CI: 1.03, 1.16), smoking duration (per 10 years, OR = 1.11, 95% CI: 1.06, 1.16), and cumulative smoking (per 10 pack-years, OR = 1.08, 95% CI: 1.04, 1.12). Risk decreased with later age at smoking initiation (per year, OR = 0.97, 95% CI: 0.96, 0.98) but not greater time since smoking cessation. Exposures to passive smoking during childhood (OR = 1.24, 95% CI: 1.03, 1.48) and from a spouse during adulthood (OR = 1.30, 95% CI: 1.03, 1.63) were independently associated with increased NPC risk in never-smoking men and women, but exposure-response trends were not observed. In conclusion, active and passive tobacco smoking are associated with modestly increased risk of NPC in southern China; risk is highest among long-term smokers.
Dai JY, Tapsoba Jde D, Buas MF; BEACON Consortium, Risch HA, Vaughan TL.
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.
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.
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.
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.
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.
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.
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
BACKGROUND & AIMS: Gluteofemoral obesity (determined by measurement of subcutaneous fat in the hip and thigh regions) could reduce risks of cardiovascular and 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.
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.
Esophageal adenocarcinoma (EA) is a rapidly fatal cancer with rising incidence in the developed world. Most EAs arise in a metaplastic epithelium, Barrett’s esophagus (BE), which is associated with greatly increased risk of EA. One of the key risk factors for both BE and EA is chronic gastroesophageal reflux disease (GERD). This study used the linkage disequilibrium (LD) score regression and genomic profile risk scoring approaches to investigate the contribution of multiple common single-nucleotide polymorphisms (SNPs) to the risk of GERD, and the extent of genetic overlap between GERD and BE or EA. Using LD score regression, we estimated an overall phenotypic variance of 7% (95% CI 3-11%) for GERD explained by all the genotyped SNPs. A genetic correlation of 77% (s.e. = 24%, P = 0.0012) between GERD and BE and 88% between GERD and EA (s.e. = 25%, P = 0.0004) was estimated using the LD score regression approach. Results from the genomic profile risk scoring approach, as a robustness check, were broadly similar to those from the LD score regression. This study provides the first evidence for a polygenic basis for GERD and supports for a polygenic overlap between GERD and BE, and GERD and EA.
Liu Z, Chang ET, Liu Q, Cai Y, Zhang Z, Chen G, Xie SH, Cao SM, Shao JY, Jia WH, Zheng Y, Liao J, Chen Y, Ernberg I, Vaughan TL, Adami HO, Huang G, Zeng Y, Zeng YX, Ye W.
BACKGROUND: The association between oral health and risk of nasopharyngeal carcinoma (NPC) is largely unknown. Further understanding could shed light on potential pathogenic mechanisms and preventive measures.
METHODS: We conducted a population-based case-control study in southern China between 2010 and 2014. We enrolled 2528 incident NPC cases aged 20-74 years, and 2596 controls, randomly selected from the total population registers, with frequency matching to the 5-year age and sex distribution of the cases by geographic region. We interviewed subjects using a structured questionnaire inquiring about oral health indicators and potential confounding factors. We used unconditional logistic regression to estimate multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CIs).
RESULTS: A higher number of filled teeth was associated with an elevated risk of NPC. Individuals with 1 to 3 and more than 3 teeth filled versus none had adjusted ORs of 1.25 (95% CI: 1.06, 1.49) and 1.55 (95% CI: 1.13, 2.12), respectively (P trend = 0.002). Conversely, the adjusted OR for those who brushed teeth twice or more per day vs. once or less per day was 0.62 (95% CI: 0.55, 0.70). We detected a borderline significant positive association with earlier age at first adult tooth loss.
CONCLUSIONS: Our study suggested a positive association between some indicators of poor oral health and risk of NPC. Further studies are needed to confirm whether the findings are causal and, if so, to further explain the underlying mechanisms.
IMPACT: Improvement of oral hygiene might contribute to reducing NPC risk
On that sentiment we can probably all agree; however, the details tend to be more elusive. For more than half a century, cancer epidemiologists and other scientists have attempted to understand the role of diet in the etiology of cancer, much of it focused on gastrointestinal (GI) cancers. Haenszel and Kurihara made groundbreaking observations on Japanese migrants to the United States, finding that the incidence of colorectal cancer in the migrants and their immediate offspring increased rapidly from the low rates in Japan to approach, and even exceed, the much higher rates in their new home. These large changes (approximately 250% in males) over a short period of time have been interpreted to reflect the importance of environmental exposures later in life in the etiology of colorectal cancer, perhaps via adoption of a more Western lifestyle, including dietary patterns. Similarly, studies of esophageal squamous cell carcinoma among migrants from high incidence (eg, China) to low incidence areas have indicated a change in incidence (in this case, reduction) among descendants over time toward that of the host country, with the speed of change depending somewhat on the country of origin and the prevalent risk factors in that country. In contrast, gastric cancer rates, which are quite high in Japan, change only very slowly among migrants in the direction of the new host country, taking multiple subsequent generations, suggesting that for gastric cancer, factors earlier in life (eg, Helicobacter pylori infection) and genetics are equally important. How far have we come since these early studies? A PubMed search showed more than 8000 publications related to diet and GI cancer, of which almost 2000 were in the past 5 years alone. Based on sheer numbers, it would seem that we already should have reached the promised land, where an individual in the general population or one at high risk for a specific GI cancer would be offered a simple chemopreventive pill, or a clear dietary recommendation, with the expectation of substantial beneficial results. Society also would be facilitating healthy nutrition choices. Unfortunately, we are not in such a land. What is taking so long?