Exploring the Etiology of Esophageal Squamous Cell Carcinoma in the Cohort Consortium

Standalone Project

(N/A)

Core funding from Imperial College London and additional funding will be sought from other sources.

Esophageal cancer is the eight most common cancer worldwide and the sixth most common cause of cancer death. Esophageal squamous cell carcinoma (ESCC) comprises 85% of all cases worldwide (Morgan et al. 2022), with esophageal adenocarcinoma (EAC) making up the remainder. ESCC and EAC have very distinct risk factors, trends in incidence and geographic distribution. The global distribution of ESCC is one of the most uneven of all cancers, with regions of high incidence across Asia from China to Iran, across east Africa from Somalia to South Africa and through South America from southern Brazil across Uruguay and Argentina (Murphy et al. 2017).
ESCC prevention research is made particularly compelling because of the rapidly fatal course of the disease and the late stage at presentation. Five-year survival rates from esophageal cancer in the USA are close to 20% (Siegel, Miller, and Jemal 2016), 12% in Europe (De Angelis et al. 2014) but less than 5% in low resource settings (Dawsey et al. 2010). Screening for early ESCC lesions (moderate to severe dysplasia) has been very successful in China, but it is not feasible in most other high incidence regions. Efforts to prevent ESCC in regions of extraordinary incidence require an understanding of the most relevant risk factors.
In regions of low incidence alcohol and tobacco are strong risk factors for ESCC (Tuyns 1983), but well powered studies of these important risk factors are rare (Lubin et al. 2012). In high incidence regions like China and Iran, these risk factors are less prevalent and have not been found to contribute significantly to the extraordinary rates (Murphy et al. 2017). Other factors like diet, air pollution appear to be universal risk factors for ESCC. Substantial and unexplained disparities by sex, socioeconomic position and race/ethnicity have been reported for ESCC incidence and prognosis (Xie and Lagergren 2018). The global average of male-to-female incidence ratio of ESCC is 2.7:1 but this figure masks significant variation with the same ratio of 1.2:1 in northern Africa and western Asia but 7.8:1 in eastern Europe (Xie and Lagergren 2018), this sex ratio has also limited what we can learn about ESCC risk factors in women in any single analysis.
Lower socioeconomic position is a consistent ESCC risk factor whether in China (Tran et al. 2005), the USA (Gammon et al. 1997), or the UK (Cooper et al. 2009) and the burden of ESCC tends to be highest in black communities and lowest in white communities (Cooper et al. 2009). While ESCC incidence is declining in the UK and USA (Offman, Pesola, and Sasieni 2018) it is not yet known whether these declines affect all social groups or whether disparities remain persist.

To further define the etiology of ESCC focusing on both traditional behavioral, dietary and environmental risk factors.

Research Questions
1. Are tobacco smoking and alcohol drinking defined by socioeconomic position or social group in driving ESCC risk? It is widely assumed that socioeconomic position may act as a risk factor by defining exposure to tobacco and alcohol but studies to date have been underpowered to look at this in combinatorial analyses.

2. Can we better define the aspects of poor diet that are associated with higher risk of ESCC? Additional, as yet poorly defined, factors may also contribute to risk. In high incidence areas like China we understand that specific dietary deficiencies (such as selenium) or excesses significantly determine risk of ESCC but in low incidence settings the contribution of diet is not well defined.

3. Do serologic signatures of inflammation and/or metabolism reflect tobacco smoking and alcohol drinking habits? If tobacco and alcohol are driving risk of ESCC are these exposures mirrored in inflammatory and metabolic markers? Are the same serologic profiles from non-smokers and non-drinkers significantly different?

1) To investigate how known risk factors (smoking, alcohol and poor diet) for ESCC are influenced by age, sex, race/ethnicity and socioeconomic position.
2) Explore how diet, lifestyle and the environment relate to ESCC risk.
3) To investigate whether ESCC risk is associated with a metabolic/inflammatory profile and possible variations in this profile by risk factor and/or social group.

Aims 1 and 2 will be addressed in a pooled analyses of existing available cohort data, using a nested case-control design. Addressing Aim 3 will involve laboratory analyses of biological samples from cases and matched controls. We will apply for grant support to address Aims 1 and 2 on approval of the proposal and once a sufficient number of Cohorts agree to participate. Aim 3 will require more substantial grant funding.

Specific Aims 1 & 2: Analytic Plan
We will pool data from participating cohorts in a nested case-control design, with controls frequency matched to cases (1:5) by age, sex and geographic region of residence. Additional matching factors may be considered as appropriate.
ESCC cases will be identified by ICD-10 (C15.0-15.9) and histology code (ICD-0: 8070, 8071, 8072, 8074, 8083). Controls will be alive and cancer free at the time of corresponding ESCC case diagnoses.
Requested variables will include age, sex, socioeconomic position (income where available, relevant small area statistics, education and occupation), tobacco, alcohol, comorbidities, self-reported health, family history of cancer, physical activity, dietary variables and anthropometry. Where available, baseline lab measurement (CBC, lipid panel, etc).
Specific Aim 3: Analytic Plan
Addressing specific aim 3 is contingent on securing additional funding to support the analysis of plasma/serum samples for the measurement of metabolic and inflammatory profiles. Specific aims 1 and 2 would be addressed first, so that the results from these analyses can inform the choice of target and platform used to address aim 3.

Tobacco and alcohol have been reported as the most significant risk factors for ESCC in regions of low incidence. By definition, studies in low incidence regions tend to have small case numbers limiting the subgroup analysis meaning that we do not fully understand how these risk factors operate among population subgroups and what additional risk factors might further contribute to risk among certain populations. Understanding the contribution of each risk factor is important to driving prevention and early detection efforts even in low incidence settings but better definition of risk factors from this rich resource might also help us to understand drivers of ESCC in regions with a high burden of disease where less data is available, such as east Africa.

10

Incident ESCC; overall mortality and mortality from ESCC

Tobacco, alcohol, comorbidities, self-reported health, family history of cancer, physical activity, dietary variables and anthropometry.

Age, sex, race/ethnicity, socioeconomic position (income where available, relevant small area statistics, education and occupation), baseline lab measurement (CBC, lipid panel, etc) if available and any existing measurements relating to inflammation or metabolism.

No