This opinion piece quantifies limitations of current approaches to prevention of esophageal adenocarcinoma, comparing the lost cases to the lost army of Napoleon during the March on Moscow in 1812 – 1813. We suggest a more rigorous approach – precision prevention – in which the population is stratified by absolute risk and risk-appropriate prevention, screening and treatments are applied.
Vaughan TL, Fitzgerald RC
The incidence of oesophageal adenocarcinoma has risen rapidly over the past four decades. Unfortunately, treatments have not kept pace; unless their cancer is identified at a very early stage, most patients will not survive a year after diagnosis. The beginnings of this widespread problem were first recognized over 25 years ago, yet rates have continued to rise against a backdrop of much improved understanding and management of oesophageal adenocarcinoma. We estimate that only ~7% of the 10,000 cases of oesophageal adenocarcinoma diagnosed annually in the USA are identified through current approaches to cancer control, and trace pathways by which the remaining 93% are ‘lost’. On the basis of emerging data on aetiology and predictive factors, together with new diagnostic tools, we suggest a five-tier strategy for prevention and control that begins with a wide population base and triages individuals into progressively higher risk strata, each with risk-appropriate prevention, screening and treatment options.
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