At the May BEACON workshop the attached slides from Dr. Gabriel Lai from NCI were presented to update BEACON members on current FOAs (funding opportunity announcement), grantsmanship resources and upcoming meetings and webinars.
A new PAR (PAR-16-131: Emerging Questions in Cancer Systems Biology (U01) (http://grants.nih.gov/grants/guide/pa-files/PAR-16-131.html ) has been announced that includes certain population sciences issues. The first round of submissions to the new PAR are due June 24, 2016, and there will be 5 more submission dates through 2018.
A pre-submission webinar will be held this Wed. April 27th from 3-4 pm EST. For more details see: https://grants.nih.gov/grants/guide/notice-files/NOT-CA-16-036.html
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.
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.
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.
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.
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.