New BETRNet Funding Opportunity

NCI has approved a new funding opportunity for BETRNet (Barett’s Esophagus Translational Research Network.) While the FOA has not yet been published, the presentation to the Board of Scientific Advisors can be downloaded by clicking here, and the notice of intent to publish is here.

BEACON paper shows shared GERD/Barrett’s genetic background

Lead authors on the following manuscript were Puya Gharahkhani and Stuart McGregor at QIMR Berghofer Medical Research Institute in Brisbane, Australia.

Hum Mol Genet. 2015 Dec 23. pii: ddv512. [Epub ahead of print]

Chronic gastroesophageal reflux disease shares genetic background with esophageal adenocarcinoma and Barrett’s esophagus.

Gharahkhani P, Tung J, Hinds D, Mishra A; Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Vaughan TL, Whiteman DC, MacGregor S, BEACON study investigators; Barrett’s and Esophageal Adenocarcinoma Consortium BEACON.

Collaborators (16)

Abstract

DSC_0008

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.

snip_20160217143919

BEACON GWAS analysis of MHC region approved

Claire Palles and Ian Tomlinson, from Wellcome Trust and Oxford, have been approved to use BEACON GWAS data as part of a larger consortium to investigate and fine map the previously reported signal at the MHC region to determine whether classical HLA alleles or amino acid positions can explain the association. BEACON members can access the proposal on the member page.

pallesian

Androgen pathway genes and risk of Barrett’s and esophageal adenocarcinoma

Int J Cancer. 2015 Sep 28. doi: 10.1002/ijc.29863. [Epub ahead of print]

Published: Polymorphisms in genes in the androgen pathway and risk of Barrett’s esophagus and esophageal adenocarcinoma.

Ek WE1,2, Lagergren K3, Cook M4, Wu AH5, Abnet CC6, Levine D7, Chow WH8, Bernstein L9, Risch HA10, Shaheen NJ11, Bird NC12, Corley DA13, Hardie LJ14, Fitzgerald RC15, Gammon MD16, Romero Y17, Liu G18, Ye W19, Vaughan TL20, MacGregor S2, Whiteman DC21, Westberg L22, Lagergren J3,23.

 Abstract

lagergren

Jesper Lagergren

The strong male predominance in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p?=?0.002) and in males (p?=?0.003), but not in females separately (p?=?0.3). This association was found in tobacco smokers (p?=?0.003) and in BE patients without reflux (p?=?0.004), but not in nonsmokers (p?=?0.2) or those with reflux (p?=?0.036). SNPs within JMJD1C were associated with risk of EAC in females (p?=?0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.

Published: Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways

PLoS One. 2015 Sep 25;10(9):e0138738. doi: 10.1371/journal.pone.0138738. eCollection 2015.

Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett’s Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium.

Lagergren K1, Ek WE2, Levine D3, Chow WH4, Bernstein L5, Casson AG6, Risch HA7, Shaheen NJ8, Bird NC9, Reid BJ10, Corley DA11, Hardie LJ12, Wu AH13, Fitzgerald RC14, Pharoah P15, Caldas C16, Romero Y17, Vaughan TL18, MacGregor S19, Whiteman D20, Westberg L21, Nyren O22, Lagergren J23.

Abstract

BACKGROUND:  The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett’s oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute.

METHODS:  This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS).

RESULTS:  Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only.

CONCLUSION:  Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.

PMID:26406593 PMCID:PMC4583498