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

Pleiotropic analysis of cancer risk loci on esophageal adenocarcinoma

Cancer Epidemiology Biomarkers and Prevention. 2015 Sep 12. pii: cebp.0596.2015. [Epub ahead of print]

Pleiotropic analysis of cancer risk loci on esophageal adenocarcinoma risk.

Lee E, Stram D, Ek WE, Onstad LE, Macgregor S, Gharahkhani P, Ye W, Lagergren J, Shaheen NJ, Murray LJ, Hardie LJ, Gammon MD, Chow WH, Risch HA, Corley DA, Levine DM, Whiteman DC, Bernstein L, Vaughan TL, Wu A.

Abstract

wu

Anna Wu

BACKGROUND:  Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett’s esophagus (BE).

METHODS:  We examined the associations between risks of EA and BE and 387 single nucleotide polymorphisms (SNPs) that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 BE) case patients from the Barrett’s and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn.

RESULTS:  After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or BE. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed.

CONCLUSIONS:Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or BE.

IMPACT:  To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and BE.

Copyright © 2015, American Association for Cancer Research.

Reflux and FOXP1 genotype interact in development of Barrett’s

Cancer Epidemiology Biomarkers and Prevention. 2015 2015 Sep 16. pii: cebp.0507.2015. [Epub ahead of print]

A newly identified susceptibility locus near FOXP1 modifies the association of gastroesophageal reflux with Barrett’s esophagus.

Dai JY, Tapsoba JD, Buas MF, Onstad LE, Levine DM, Risch HA, Chow JW, Bernstein L, Ye W, Lagergren J, Bird NC, Corley DA, Shaheen NJ, Wu AH, Reid BJ, Hardie LJ, Whiteman DC, Vaughan TL.

Abstract

dai

James Dai

BACKGROUND: Important risk factors for esophageal adenocarcinoma (EA) and its precursor, Barrett’s esophagus (BE) include gastroesophageal reflux disease, obesity, and cigarette-smoking. Recently, genome-wide association studies have identified seven germline single nucleotide polymorphisms (SNPs) that are associated with risk of BE and EA. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear.

METHODS: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1516 EA case patients, 2416 BE case patients, and 2187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate odds ratios for these risk factors stratified by SNP genotype, separately for BE and EA.

RESULTS: The odds ratio for BE associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal p-value=0.0005, false discovery rate=0.042). Odds ratios (95% confidence intervals) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91,7.56), 3.56 (2.85,4.44), and 3.97 (2.47,6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index.fig2

CONCLUSIONS: Reflux symptoms are more strongly associated with BE risk among persons homozygous for the major allele of rs2687201, which lies ~75 kb downstream of the transcription factor gene FOXP1.

IMPACT: The novel gene-exposure interaction discovered in this study provides new insights to the etiology of esophageal adenocarcinoma.

Copyright © 2015, American Association for Cancer Research.

BEACON Workshop 2016 – Save the Date

Thanks to Linda Liao and heWP_20150520_15_23_41_Raw 300dpir colleagues at NCI for hosting the very successful BEACON workshop at the NCI Shady Grove Campus in May 2015.

The next workshop is scheduled for May 25-26 2016 in Oakland, hosted by Doug Corley. These dates are immediately following the DDW meeting in San Diego. Hotel information has been distributed, and additional information will follow.

Age-Specific Risk Factors for Esophageal Adenocarcinoma

Int J Cancer. 2015 Jul 14. doi: 10.1002/ijc.29688. [Epub ahead of print]

Age-specific risk factor profiles of adenocarcinomas of the esophagus: A pooled analysis from the international BEACON consortium.

Drahos J, Xiao Q, Risch HA, Freedman ND, Abnet CC, Anderson LA, Bernstein L, Brown L, Chow WH, Gammon MD, Kamangar F, Liao LM, Murray LJ, Ward MH, Ye W, Wu AH, Vaughan TL, Whiteman DC, Cook MB

Abstract

drahos

Jennifer Drahos

Esophageal (EA) and esophagogastric junction (EGJA) adenocarcinoma have been steadily increasing in frequency in younger people, however the etiology of these cancers is poorly understood. We therefore investigated associations of body- mass index (BMI), cigarette smoking, alcohol consumption, gastroesophageal reflux, and use of non-steroidal anti-inflammatory drugs (NSAIDs) in relation to age-specific risks of EA and EGJA.

We pooled individual participant data from eight population-based, case-control studies within the international Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON). The analysis included 1,363 EA patients, 1,472 EGJA patients, and 5,728 control participants. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for age-specific (<50, 50-59, 60-69, ?70 years) cancer outcomes, as well as interactions by age. BMI, smoking status and pack-years, recurrent gastroesophageal reflux, and frequency of gastroesophageal reflux were positively associated with EA and EGJA in each age group. Early-onset EA (<50 years) had stronger associations with recurrent gastroesophageal reflux (OR=8.06, 95%CI: 4.52, 14.37; Peffect modification =0.01) and BMI (ORBMI ?30 vs. <25 =4.19, 95%CI: 2.23, 7.87; Peffect modification =0.04), relative to older age groups. In contrast, inverse associations of NSAID use were strongest in the oldest age group (?70 years), although this apparent difference was not statistically significant. Age-specific associations with EGJA showed similar, but slightly weaker patterns and no statistically significant differences by age were observed. Our study provides evidence that associations between obesity and gastroesophageal reflux are stronger among earlier onset EA cancers.