Led by post-doctoral research fellow, Aaron Thrift, this manuscript uses a technique called Mendelian randomization to add support to the hypothesis that obesity is causally related to Barrett’s esophagus and esophageal adenocarcinoma. Aaron recently joined the faculty of Baylor University where he is an assistant professor of epidemiology.
Thrift AP, Shaheen NJ, Gammon MD, Bernstein L, Reid BJ, Onstad L, Risch HA, Liu G, Bird NC, Wu AH, Corley DA, Romero Y, Chanock SJ, Chow WH, Casson AG, Levine DM, Zhang R, Ek WE, MacGregor S, Ye W, Hardie LJ, Vaughan TL, Whiteman DC.
BACKGROUND: Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE). However, the relationships may be affected by bias and confounding.
METHODS: We used data from the Barrett’s and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided.
RESULTS: The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m(2) increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses.
CONCLUSIONS: People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.
Weronica Ek (Karolinska) and Stuart MacGregor (QIMR-Berghofer) led this analysis which found that genetics accounts for 25 – 35% of the variability in Barrett’s and esophageal adenocarcinoma, and that most of the genetic influence occurs in the development of Barrett’s rather than the progression to cancer.
Ek WE, Levine DM, D’Amato M, Pedersen NL, Magnusson PK, Bresso F, Onstad LE, Schmidt PT, Törnblom H, Nordenstedt H, Romero Y; Mayo Clinic Esophageal Adenocarcinoma and Barrett’s Esophagus Registry Consortium, Chow WH, Murray LJ, Gammon MD, Liu G, Bernstein L, Casson AG, Risch HA, Shaheen NJ, Bird NC, Reid BJ, Corley DA, Hardie LJ, Ye W, Wu AH, Zucchelli M, Spector TD, Hysi P, Vaughan TL, Whiteman DC, MacGregor S; BEACON study investigators.
BACKGROUND: Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett’s esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA.
METHODS: We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used.
RESULTS: We estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 × 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD.
CONCLUSIONS: We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.
After four years of effort on the part of our team, we published the main results from our GWAS in Nature Genetics, finding four new loci for esophageal adenocarcinoma.
David M Levine, Weronica E Ek, Rui Zhang, Xinxue Liu, Lynn Onstad, Cassandra Sather, Pierre Lao-Sirieix, Marilie D Gammon, Douglas A Corley, Nicholas J Shaheen, Nigel C Bird, Laura J Hardie, Liam J Murray, Brian J Reid, Wong-Ho Chow, Harvey A Risch, Olof Nyrén, Weimin Ye, Geoffrey Liu, Yvonne Romero, Leslie Bernstein, Anna H Wu, Alan G Casson, Stephen J Chanock, Patricia Harrington, Isabel Caldas, Irene Debiram-Beecham, Carlos Caldas, Nicholas K Hayward, Paul D Pharoah, Rebecca C Fitzgerald, Stuart MacGregor, David C Whiteman, Thomas L Vaughan
Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett’s esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett’s esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10-10) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10-9) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10-9) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett’s esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.
Clockwise from top: Dave Levine, Weronica Ek, Rui Zhang, Rebecca Fitzgerald, Stuart MacGregor, David Whiteman and Thomas Vaughan
Another manuscript from Lizzy Kantor’s dissertation work was recently published in Nutrtion and Cancer.
Nutr Cancer. 2013 Sep 20. [Epub ahead of print]
Research suggests that long-chain omega-3 polyunsaturated fatty acids (LC-PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have antineoplastic properties, yet evidence for association between LC-PUFAs and colorectal cancer (CRC) remains inconsistent. Using the VITamins And Lifestyle (VITAL) cohort, we evaluated how EPA/DHA intake, and its primary sources, fish oil supplement use and dark fish consumption, relate to CRC risk. A total of 68,109 Washington residents aged 50-76 completed a questionnaire between 2000-2002 and were followed for CRC through 2008 (n = 488). Persons using fish oil supplements on 4+ days/wk for 3+ yr experienced 49% lower CRC risk than nonusers (hazard ratio = 0.51, 95% CI = 0.26-1.00; P trend = 0.06). The association between fish oil use and decreased CRC risk was primarily observed for men (P interaction = 0.02; P trend men = 0.02; P trend women = 0.88) and for colon cancer (P difference = 0.05; P trend colon = 0.03; P trend rectum = 0.87). Although dark fish and total EPA + DHA intake were not associated with CRC risk overall, these associations varied by genetic risk (P interaction = 0.009 and 0.02, respectively), with inverse associations observed among low-moderate genetic risk groups and positive associations observed among high risk groups. Results suggest that associations between LC-PUFA intake and CRC may vary by gender, subsite, and genetic risk, providing additional insight into the potential role of LC-PUFAs in cancer prevention.
University of Washington PhD student Lizzy Kantor published the following work as part of her dissertation. Lizzy is currently a postdoc at Harvard University.
Cancer Epidemiol Biomarkers Prev. 2013 Aug 5. [Epub ahead of print]
Oxidative stress and resulting cellular damage have been suggested to play a role in the etiology of several chronic diseases, including cancer and cardiovascular disease. Identifying factors associated with reduced oxidative stress and resulting damage may guide future disease-prevention strategies. In the VITamins And Lifestyle (VITAL) biomarker-study of 209 persons living in the Seattle area, we examined the association between current use of several specialty supplements and oxidative stress, DNA damage, and DNA repair capacity. Use of glucosamine, chondroitin, fish oil, methylsulfonylmethane (MSM), co-enzyme Q10 (CoQ10), ginseng, ginkgo, and saw palmetto was ascertained by a supplement inventory/interview, while use of fiber supplements was ascertained by questionnaire. Supplements used by more than 30 persons (glucosamine and chondroitin) were evaluated as the trend across number of pills/week (non-use, <14 pills/week, 14+ pills/week), while less-commonly used supplements were evaluated as use/non-use. Oxidative stress was measured by urinary 8-isoprostane and PGF2? concentrations using enzyme immunoassays (EIA), while lymphocyte DNA damage and DNA repair capacity were measured using the Comet assay. Multivariate-adjusted linear regression was used to model the associations between supplement use and oxidative stress/DNA damage. Use of glucosamine (p-trend:0.01), chondroitin (p-trend:0.003), and fiber supplements (p:0.01) was associated with reduced PGF2? concentrations, while CoQ10 supplementation was associated with reduced baseline DNA damage (p:0.003). Use of certain specialty supplements may be associated with reduced oxidative stress and DNA damage. Further research is needed to evaluate the association between specialty supplement use and markers of oxidative stress and DNA damage.
The science writer, Carl Zimmer, recently highlighted the findings from our NSAIDs and clonal evolution paper that was recently published in PLoS Genetics. Ths paper was part of Rumen Kostadinov’s dissertation at the University of Pennsylvania, with Carlo Maley as senior author.
Also recently mentioned in the NY Times wellness blog: