Environment International 157 (2021) 106880

Available online 17 September 20210160-4120/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

A concise review towards defining the exposome of oesophageal cancer in sub-Saharan Africa

Trancizeo Lipenga a,b,c,d,*, Limbikani Matumba c,e, Arnau Vidal a,c, Zdenko Herceg f, Valerie McCormack g, Sarah De Saeger a,c,d,h, Marthe De Boevre a,c,d

a Department of Bioanalysis, Centre of Excellence in Mycotoxicology and Public Health, Ghent University, Ghent, Belgium b Department of Pathology, Kamuzu University of Health Sciences (KUHeS), Blantyre, Malawi c MYTOX-SOUTH, International Thematic Network, Ghent University, Ghent, Belgium d CRIG, Cancer Research Institute Ghent, Ghent, Belgium e Food Technology and Nutrition Research Group-NRC, Lilongwe University of Agriculture and Natural Resources, Lilongwe, Malawi f Epigenomics and Mechanism Branch, International Agency for Research on Cancer (WHO-IARC), Lyon, France g Environment and Lifestyle Epidemiology Branch, International Agency for Research on Cancer (WHO-IARC), Lyon, France h Department of Biotechnology and Food Technology, Faculty of Science, University of Johannesburg, Doornfontein Campus, Gauteng, South Africa

A R T I C L E I N F O

Handling Editor: Olga Kalantzi

Keywords: Oesophageal cancer Oesophageal squamous cell carcinoma Exposome Africa Environmental health

A B S T R A C T

Context: Oesophageal cancer (EC) is among the common causes of illness and death among all cancers world-wide. Advanced EC has a poor prognosis, with worse outcomes observed in low-income settings. Oesophageal squamous cell carcinoma (ESCC) is the most common EC histology reported globally, with the highest ESCC incidence rates in the ‘Asian Belt’ and the African EC corridor. While the aetiology of ESCC is well-documented in the ‘Asian belt’, data for the African EC corridor and the entirety of sub-Saharan Africa (SSA) are fewer. Objective: To help address gaps in ESCC aetiology in SSA, we critically evaluated evidence of lifestyle, envi-ronmental, and epigenetic factors associated with ESCC risk and discussed prospects of defining ESCC exposome. Data inclusion: Unlimited English and non-English articles search were made on PubMed Central and Web of Science databases from January 1970 to August 2021. In total, we retrieved 999 articles and considered meta- analyses, case-control, and cohort studies. The quality of individual studies was assessed using the New-castle–Ottawa scale. Data extraction: Details extracted include the year of publication, country of origin, sample size, comparators, outcomes, study subjects, and designs. Data analysis: Together, we assessed 13 case-control studies and two meta-analyses for the effect of lifestyle or environmental exposures on ESCC risk. Again, we evaluated seven case-control studies and one meta-analysis regarding the role of epigenetics in ESCC tumorigenesis. Results: In general, evidence of ESCC aetiology points to essential contributions of alcohol, tobacco, hot bever-ages, biomass fuel, and poor oral health/hygiene, although more precise risk characterisation remains necessary. Conclusion: We conclude that ESCC in SSA is a multifactorial disease initiated by several external exposures that may induce aberrant epigenetic changes. The expanding aetiological research in this domain will be enhanced by evidence synthesis from classical and molecular epidemiological studies spanning the external and internal exposome.

1. Introduction

Oesophageal cancer (EC) causes over 544,000 deaths worldwide annually, making it the sixth leading cause of mortality and the seventh cause of morbidity among all cancers (Sung et al., 2021). Among EC

histological types, oesophageal squamous cell carcinoma (ESCC) is the most prevalent subtype worldwide, accounting for more than 85% of all ESCC cases (Sung et al., 2021; Wild et al., 2020). The advanced stage of ESCC has a poor prognosis with worse outcomes observed in the low-and middle-income settings (Asombang et al., 2019; Murphy et al., 2017),

* Corresponding author at: Department of Bioanalysis, Centre of Excellence in Mycotoxicology & Public Health, Ottergemsesteenweg 460, 9000 Ghent, Belgium. E-mail address: trancizeo.lipenga@ugent.be (T. Lipenga).

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https://doi.org/10.1016/j.envint.2021.106880 Received 12 May 2021; Received in revised form 11 September 2021; Accepted 13 September 2021

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partly reflecting financial constraints, poor health infrastructure, and the late occurrence of ESCC symptoms. Still more, the prognosis is far from excellent even in high-income settings (Murphy et al., 2017).

ESCC incidence shows a large geographical variation (Sung et al., 2021), with the “Asian Belt” encompassing a region that stretches from eastern to central Asia and the “African EC corridor” stretching along the easterly part of the African continent (Fig. 1). In sub-Saharan Africa (SSA), ESCC age-standardised incidence rates (ASRs) are highest in Malawi, Kenya, and Uganda, Fig. 1 (Arnold et al., 2015). ESCC incidence rates outside of East and Southern Africa are low, probably suggesting the confines of ESCC risk factors along the Africa Rift Valley due to the influence of topography and geochemistry (Schaafsma et al., 2015).

Worldwide, several external exposures are implicated in ESCC pathogenesis. In the Asian Belt, opium use (Nasrollahzadeh et al., 2008), drinking un-piped water (Golozar et al., 2016; Sheikh et al., 2019), poor diet (Sheikh et al., 2019; Tran et al., 2005), hot tea intake (Sheikh et al., 2019; Tai et al., 2017; Yang et al., 2020), poor oral health (Dar et al., 2013; Sheikh et al., 2019), micronutrient deficiencies and biomass use (Sheikh et al., 2019; Steevens et al., 2010) have been attributed to the high ESCC burden in the region. While research on the aetiology of ESCC has been considerably studied in the Asian belt and surrounding areas – data for the African corridor and the entirety of the SSA region, except for South Africa (Sewram et al., 2016, 2014), is only more recently expanding.

In the current review, to help address gaps in ESCC aetiology in the SSA, we update the research landscape for lifestyle and environmental factors associated with ESCC risk, building on previous reviews (Asombang et al., 2019; McCormack et al., 2017). We further summarise known epigenetic factors and discuss prospects of expanding ESCC research via an exposome approach – the totality of exogenous expo-sures and endogenous responses accrued from early childhood resulting in pathology (Miller and Jones, 2014). Finally, we highlight and propose the integration of multi-omics data with classical epidemiology data as a holistic means of studying ESCC aetiology.

2. Search strategy and data selection

Data sources: Unlimited search of English and non-English articles evaluating the association of lifestyle and environmental factors with

ESCC risk or epigenetic predisposition to ESCC risk were made on PubMed Central and Web of Science electronic databases from January 1970 to August 2021. The following search queries: ‘environmental,’ ‘lifestyle,’ ‘dietary,’ ‘xenobiotic,’ ‘genetic,’ ‘epigenetic,’ ‘external,’ ‘pre-disposing,’ ‘factors,’ ‘oesophageal cancer,’ ‘esophageal cancer,’ ‘oeso-phageal squamous dysplasia,’ ‘esophageal squamous dysplasia,’ ‘oesophageal squamous cell carcinoma,’ ‘esophageal squamous cell carcinoma,’ ‘aetiology,’ ‘incidence,’ ‘risk,’ ‘sub-Saharan Africa,’ were used individually or in combination. In total, we retrieved 999 articles from literature searches.

Inclusion and exclusion criteria: We considered meta-analyses, case- control, and cohort studies. The quality of individual studies was assessed using the Newcastle–Ottawa Scale (NOS), (Ottawa Hospital, n. d.). Articles with a minimum score of one in either of the NOS elements were considered. Studies with clear ESCC diagnosis confirmed by his-tology, endoscopy, image visualisation, or clinical diagnosis, i.e. dysphagia and weight loss, met the inclusion criteria. We included studies that had minimally adjusted for age and sex. We excluded pub-lications that did not establish an association between external factors or predisposing factors with ESCC risk. TL evaluated the eligibility of retrieved data, then presented the eligible studies to LM, AV, ZH, VAM, SDS, and MDB for further review. Any disagreements were highlighted and resolved through dialogue.

Data extraction: Details of extracted data include the year of publi-cation, study design, country of origin, sample size, study subjects, comparators, outcomes, and statistical analyses. We reported ESSC risk with a generic term relative risk (RR), but studies estimated odds ratio (OR), hazard ratio (HR), relative risk (RR), or attributable population fraction (PAF) depending on the design. Statistical measures were re-ported in a fully adjusted model when an unadjusted model was also presented.

3. ESCC lifestyle and environmental factors (specific external exposome)

Below, we present the studies investigating the association between specific external exposures and the risk of ESCC in SSA (Table 1). Within this synthesis for SSA, for comparative purposes, we have also noted the magnitude of associations from any relevant seminal studies conducted

Fig. 1. ESCC age-standardised incident rates, ASR, in women and men across Africa (Arnold et al., 2015). High ESCC ASRs are observed easterly of the African continent ‘the African ESCC corridor’.

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worldwide (Table S1).

3.1. Alcohol

While the role of alcohol in ESCC pathogenesis was less studied in the 20th century in SSA, there has been accumulative evidence recently (Table 1). An increased ESCC incidence rate due to alcohol consumption in the SSA region may be related to specific behaviours such as early age at onset of alcohol intake and the ready availability of cheap forms of alcoholic beverages (Fig. 2b).

In SSA, frequency, duration, and forms of alcoholic beverages in-fluence ESCC risk, and consumption is particularly high in some lower socioeconomic male groups. In a case-control study in western Kenya (Menya et al., 2019a), involving 422 ESCC confirmed cases and 414 controls, there was an overall 48% PAF for taking more than two alco-holic drinks per day and it was highest in men. Past and current drinkers had more than 2-fold ESCC risk compared to non-consumers. In a separate hospital-based case-control study in the rift valley region of Kenya (Patel et al., 2013), involving 147 ESCC patients and 159 controls, alcohol consumption was associated with an increased ESCC risk (RR

Table 1 Lifestyle or environmental risk factors, SSA.

Country, region Study design

Cases/ control

Recruitment period (years)

Risk factor(s) Reference

South Africa, Johannesburg

Case- control

267/804 1995 – 1999 Tobacco: [All current smokers, ESCC risk↑], [Ex-smokers, ESCC risk ↑], [ ≥15 g/ day tob. smoking, ESCC risk↑↑], [ ≤ 15 g/day tob. use, ESCC risk ↑]

(Pacella-Norman et al., 2002)

Alcohol: [Freq. alc. Intake, ESCC risk ↑] [Occasional drinking ↓↓] South Africa, East

Cape Province Case- control

670/1188 2001 – 2003 Diet: [green leafy vegetables 5–7 days/wk in ♂ and ♀, ESCC risk ↓↓], [Increase intake of Φ in ♀, ESCC risk↓↓]

(Sewram et al., 2014)

South Africa, East Cape Province

Case- control

670/1188 2001 – 2013 Tobacco: [Ever Tob. Smoking, ESCC risk ↑], [14.5 g total tobacco/day, ESCC risk↑↑]; [1–7 g total tobacco/day, ESCC risk ↑], [Pipe smoking, ESCC risk ↑]; [Commercial cig. Smoking ESCC risk ↑]; [Hand-rolled cig. Smoking, ESCC risk, ↑]

(Sewram et al., 2016)

Alcohol: [Alc. Intake in ♂ and ♀, ESCC risk ↑]; [Home-made spirits vs never, ESCC risk ↑↑↑]; [3.01 + litres/week maize beer, ESCC risk ↑↑]; [>2 L/week commercial beer, ESCC risk ↑]; [ > 52.8 g Ethanol intake/day, ESCC risk ↑↑]

Kenya, Eldoret Case- control

147/159 2003 – 2006 Tobacco: [Tob. smoking, ESCC risk ↑] (Patel et al., 2013)

Alcohol: [Alc. Intake, ESCC risk ↑] Biomass Fuel: [Cooking on firewood/charcoal, ESCC risk↑] Poor oral health: [Tooth loss, ESCC risk ↑↑] Hot beverages: [Hot drinks (tea or uji), ESCC risk ↑↑]

Uganda, Mbarara Case- control

67/142 2003 – 2014 Tobacco: [Tobacco smoking PAF, ESCC risk ↑] (Okello et al., 2016)

Alcohol: [Alc. Intake PAF, ESCC risk ↑] Africa and other

continents Meta- analysis

n.a. 2000 – 2019 Biomass fuel: [Pooled biomass use in Africa, ESCC risk ↑] (Okello et al., 2019)

Africa Meta- analysis

n.a. up to 2019 Alcohol: [Alc. in take, ESCC risk ↑] Tobacco: [Tob. usage, ESCC risk ↑]

(Asombang et al., 2019)

Zambia, Lusaka Case- control

77/145 2011 – 2012; 2013 – 2014

Viral infection: [HPV seropositivity, ESCC risk↑] (Kayamba et al., 2015)

Malawi, Lilongwe & Blantyre

Case- control

96/180 2011 – 2013 Tobacco: [Ever Cig. Smoking, ESCC risk ↑↑] (Mlombe et al., 2015)

Biomass fuel: [Firewood cooking, ESCC risk ↑↑] Diet and mycotoxin contamination: [Milled dehulled maize (white maize flour), ESCC risk ↑↑], [Milled whole-grain milled (M’gaiwa), ↑]

Zambia, Lusaka Case- control

50/50 2013 – 2014 Tobacco: [Cig. Smoking, ESCC risk ↑↑] (Kayamba et al., 2015)

Biomass fuel: [Charcoal/firewood, ESCC risk ↑] Tanzania, Dar es

Salaam Case- control

471/471 2013 – 2015 Tobacco: [Former smoking, ESCC risk ↑], [Second-hand smoke in the household, ESCC risk ↑] Diet: [Daily consumption of fruits, ESCC risk ↓↓], [Daily consumptions of raw greens, ESCC risk ↓↓↓], [Daily consumption of smoked fish, ESCC risk ↓↓↓] Others: [Daily use of spicy chilies, ESCC risk ↑], [Daily intake of salted foods, ESCC risk ↑]

(Mmbaga et al., 2021b)

Ethiopia, Arsi & Bale Case- control

215/245 2015 Hot food: [Hot porridge, ESCC risk ↑] (Shewaye and Seme, 2016)

Kenya, Eldoret Case- control

430/440 2013 – 2018 Alcohol: [Alc. Ever drinking plus tob. smoking, ESCC risk ↑↑], [Alc..ever drinking, ESCC risk ↑], [>2 alc. Drinks/day PAF, ESCC risk ↑↑], [Past and recent alc. Drinkers, ESCC risk ↑]

(Menya et al., 2019a)

Poor oral health: [Arak tree (mswaki) stick use, ESCC risk ↑]; [≥ 2 teeth brushing/ week, ESCC risk ↓↓ ], [≥ 2 missing teeth, ESCC risk ↑], [ ≥ 1 decay teeth, ESCC risk ↑], [Severe/moderate dental fluorosis, ESCC risk ↑↑]

(Menya et al., 2019b)

Unpiped water: [Using well, spring, or river water, ESCC risk ↑] Hot beverages: [Drinking ‘extremely hot’ and ‘hot tea’, ESCC risk ↑] (Middleton et al.,

2019) Tanzania,

Kilimanjaro Case- control

310/313 2015 – 2019 Poor oral health: [Chewed stick teeth brushing, ESCC risk ↑]; [DMFT index ≥ 10 versus 0, ESCC risk ↑]; [TF1 5 + vs 0, ESCC risk↑↑↑]; [Less than daily tooth brush, ESCC risk ↑]; [≥1 missing teeth, ESCC ↑]; [≥ 1 decayed teeth, ESCC risk ↑]

(B. T. Mmbaga et al., 2021a)

Ethiopia, Arsi Case- control

104/208 2019 – 2020 Hot food and beverage: [Very hot porridge, ESCC risk ↑]; [Large volume of coffee, ESCC ↑↑]; [Eating porridge fast, ESCC risk ↑↑]

(Deybasso et al., 2021)

Abbreviations: ESCC, oesophageal squamous cell carcinoma; ↔, No effect; ↑*, Borderline increased effect; ↓*, Borderline reduced effect; Φ, Dietary pattern containing sorghum, green leafy vegetables, green legumes, fruits, and meat; vs, versus; ↑, OR/RR/HR 1–4 or PAF 1–17%; ↑↑, OR/RR/HR 5–9 or PAF 18–34%; ↑↑↑, OR/RR/HR ≥10 or PAF ≥ 35%; ↓, 0–29% reduced odds; ↓↓, 30–59% reduced odds; ↓↓↓, > 60% reduced odds; PAF, Population attributable fraction; Alc., Alcohol; Freq., Frequent; Tob., Tobacco; Cig., Cigarette; Curr., Current.; HPV, Human papillomavirus; DMFT, Decay + missing + filling teeth; TFI Non-dental observer-assessed fluorosis index.

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Fig. 2. Snapshot of ESCC risk factors relevant for SSA. a. Hot food, in this case, porridge, is served on a plate directly from firewood at extremely high temperatures. Consumption of hot food is probably carcinogenic, with positive associations seen for ESCC (Middleton et al., 2019 Sheikh et al., 2019). b. Alcohol from spirits is a ready option for under-age individuals in African setups since there are less-stringent measures against alcohol. Thus, increased alcohol consumption from young ages is an established ESCC in Africa (Asombang et al., 2019; Menya et al., 2019a). c. Firewood is a common cooking fuel in most African settings. Fumes and smoke from the incomplete combustion of firewood are a potential ESCC risk (Kayamba et al., 2015; Mlombe et al., 2015; Patel et al., 2013). d. Charbroiling/barbecuing is regarded as a recreational activity among Africans and a norm among other tribes, i.e. the Ngoni. Smoke from burning charcoal may potentially contain carcinogens, i.e. polycyclic aromatic hydrocarbons, PAHs (Table 3). e. Tobacco smoking has been associated with ESCC burden and is an uncommon lifestyle habit in the SSA region (Mlombe et al., 2015; Okello et al., 2016; Pacella-Norman et al., 2002). f. Drinking hot tea or coffee could increase the risk of developing ESCC (Deybasso et al., 2021; Middleton et al., 2019). Hot beverage temperatures at or above 65 ◦C have been indicated to double the odds of developing ESCC risk elsewhere (Sheikh et al., 2019). g. The use of unpiped water (in this case, a well) is a common practice among rural populations. Drinking unpiped water has been with ESCC risk (Menya et al., 2019b; Sheikh et al., 2019).

Table 2 Epigenetic predisposing factors, SSA.

Country, region Study design

Cases/ control

Recruitment period (years)

Predisposing factor(s) Reference

South Africa, Cape Town

Case- control

559/904 2000 – 2010 CASP8: [variant ASP302His, ESCC risk↑], [CASP8 variant − 652 6 N Del 302H, ESCC risk ↑]

(Bye et al., 2011)

ALDH2: [variant + 82 G > A, ESCC risk ↓↓], [ALDH2 variant + 82 G − 261 T, ESCC risk ↑] MGMT: [variant Leu84Phe, ESCC risk ↑] COX-2: [variant − 765 G > C, ESCC risk ↑], [variant − 1995 A > G, ESCC risk ↓↓]

South Africa, Cape Town

Case- control

58/226 n.s. AR: [Short GGC variant of AR (GGC)≤16 or (GGC)≤14, ESCC risk ↑], [ (GAC)≤21 (GGC)>16 haplotype, ESCC risk ↓↓↓]

(Dietzsch et al., 2003)

South Africa, Cape Town

Meta- analysis

1471/1791 n.s. CHEK2: [variant rs1033667, ESCC risk ↑*] (Chen et al., 2019)

South Africa, Cape Town

Case- control

189/198 n.s. CYP2E1: [variant CYPE2*6, ESCC risk ↑] (Li et al., 2005)

South Africa, Cape Town

Case- control

238/268 1997 – 2003 ADH3: [variant ADH3*2, ESCC risk ↑↑] (Li et al., 2008)

ALDH2: [variant ALDH2*2, ESCC risk ↑] South Africa, Cape

Town Case- control

664/1709 n.s. RUNX1: [variant rs2014300, ESCC risk ↑] (Bye et al., 2012)

South Africa, Cape Town

Case- control

_ 2000 – 2010 MSH3: [variant rs26279, ESCC risk↑] (Vogelsang et al., 2012)

PMS1: [variant 5742938, ESCC risk ↑] MLH3: [variant rs28756991, ESCC risk ↑]

South Africa, Cape Town

Case- control

84/84 2008 – 2013 MSH3 methylation: [MSH3 methylation + tobacco smoking, ESCC risk↑↑↑] (Vogelsang et al., 2014)

Abbreviations: ESCC, oesophageal squamous cell carcinoma; ↔, No effect; ↑*, Borderline increased effect; ↓*, Borderline reduced effect; ↑, OR/RR/HR 1–4 or PAF 1–17%; ↑↑, OR/RR/HR 5–9 or PAF 18–34%; ↑↑↑, OR/RR/HR ≥ 10 or PAF ≥ 35%; ↓, 0–29% reduced odds; ↓↓, 30–59% reduced odds; ↓↓↓, > 60% reduced odds; PAF, Population attributable fraction; CASP8, Caspase 8 gene; ALDH2, Aldehyde dehydrogenase 2 family member; MGMT, O-6-methylguanine-DNA methyltransferase; COX-2, Cyclooxygenase-2 gene; AR, Androgen Receptor; CHEK2, Checkpoint kinase 2, gene; CYP2E1, Cytochrome P450 2E1, gene; ADH3, alcohol dehydrogenases 3 gene; RUNX1, Runt related transcription factor 1; MSH3, MutS homolog 3 gene; MLH3, MutL homolog 3 gene; PMS1, PMS1 homolog 1, mismatch repair system

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2.64, 95% CI: 1.55–4.54). Although the authors suggested a positive association between the frequency of alcohol intake and ESCC risk – they did not present the actual findings in their write-up. In a South African study (Sewram et al., 2016), involving 670 ESCC cases and 1188 con-trols, individuals consuming about two bottles of 500 mL each of alcohol per day were more likely to develop ESCC than non-drinkers (in males RR 4.72, 95% CI: 2.64–8.41 and in females RR 5.24, 95 CI: 3.34–8.23). While the researchers did not discuss the dose–response effect – within the same region (Pacella-Norman et al., 2002), a case-control study had shown a positive association between the frequency of alcohol intake and ESCC risk (RR 1.8, 95% CI: 1.2–2.8). Frequent drinkers were defined as those who reported consuming at least one type of alcoholic beverage on most days. In contrast, no significant associations were established between ESCC and alcohol or tobacco in Ethiopia (Shewaye and Seme, 2016), but alcohol drinking prevalence was low and may be under- reported. This finding may suggest a different regional prevalence of ESCC external influences. A further consideration is to review in-teractions between alcohol and other possible external exposures for the multiplicative ESCC effect. For instance, a pooled analysis of case- control and cohort studies from Asia (Prabhu et al., 2014), Table S1, has demonstrated a synergistic effect between alcohol and tobacco smoking in ESCC tumorigenesis.

Early and prolonged alcohol intake might influence ESCC tumori-genesis by exposing individuals to excessive acetaldehyde (Table 2). A high acetaldehyde content in human circulation may stimulate oeso-phageal carcinogenesis by forming DNA adducts or reactive oxygen or nitrogen species (Seitz and Stickel, 2007). Moreover, the content of alcoholic drinks may additionally include other potential carcinogens, including probable ESCC carcinogens: polycyclic aromatic hydrocar-bons (PAHs), nitrosamines, and potential ESCC carcinogens: mycotoxins (Boffetta and Hashibe, 2006; Matumba et al., 2014). Monitoring and regulating potential toxicants in raw materials and their consumption levels could help the processing of establishing maximum tolerable limits in alcoholic beverages for the formal industry. However, for informal businesses, such measures cannot be enforced. Therefore, monitoring, community engagement, and sensitisation programmes would be an ideal health preventive strategy.

3.2. Tobacco

There is growing evidence linking tobacco use and ESCC risk in SSA (Table 1). For instance, a modest population attributable fraction (PAF 16%) of ESCC was due to tobacco smoking in Uganda (Okello et al., 2016). Again, in a case-control study in Malawi (Mlombe et al., 2015), more ESCC cases were reported to have a history of tobacco smoking than non-smokers (RR 5.4, 95% CI: 2.0–15.2).

In SSA, smoking habits, including pipe smoking and smokeless to-bacco, may also carry a potential ESCC risk. In South Africa (Sewram et al., 2016), pipe-smoking was found to convey a greater ESCC risk (RR 3.21, 95% CI: 2.13–4.83) as compared to commercial cigarette smoking (RR 2.35, 95% CI: 1.59–3.49) or hand-rolled cigarette smoking (RR 2.49, 95% CI: 1.69–3.69). It is not well understood why pipe smoking could carry such a greater risk. It can only be hypothesised that carci-nogenic additive products could originate from pyrolysis products of the pipe during smoking or that pipe smoking encourages greater volume or frequency of tobacco smoking. Smokeless tobacco use in the nasal or oral cavity is also common practice in East and Southern Africa, espe-cially amongst women (Boua et al., 2021; Padrao et al., 2013; Sreer-amareddy et al., 2014), and its role in ESCC carcinogenesis – alone or in combination with smoked tobacco (Fig. 2d) – warrants further research.

Like many xenobiotics, tobacco’s role in ESCC pathogenesis is a function of the frequency/intensity and duration of tobacco usage. For example, in a case-control study in South Africa (Pacella-Norman et al., 2002), involving 267 ESCC cases and 804 controls, smoking large amounts (i.e. >15 g per day) of tobacco doubled the odds of developing ESCC in current smokers than smoking on a smaller scale (<15 g per

Table 3 Some xenobiotics associated with ESCC increased risk.*

Xenobiotic Brief literature

Polycyclic Aromatic Hydrocarbons

PAHs are toxic compounds formed from the incomplete combustion of organic materials. A high concentration of PAHs is found in tobacco and smoked meat ( Roshandel et al., 2012). Metabolic activation of PAHs into Anti-diol-epoxides and o-quinones, may mutate p53 and result in DNA adduct formation (Shen et al., 2006). Because of their toxicity, PAHs have been implicated in different cancers, including ESCC (Fagundes et al., 2006; M. J. Roth, 2001). In low-income settings, PAHs exposure may be influenced by lifestyle habits, i.e. excess use of firewood as fuel for cooking (Okello et al., 2019). In SSA, women are more likely to be exposed to PAHs than men, as it is culturally accepted that house chores (including cooking) are women’s responsibility. Indeed, household air pollution studies in Kenya showed a higher particulate matter exposure in women (Ezzati et al., 2000).

Nitrosamine Nitrosamines are genotoxic chemicals formed by the reaction of amines (Dubrow et al., 2010). Preformed nitrosamines are sourced from tobacco, beer, and smoked food while endogenous forms are made from nitrate and nitrite (Paula Jakszyn and lez, 2006). Despite satisfactory evidence of nitrosamine and its metabolites’ involvement in gastric cancer, its role in ESCC pathogenesis is suggestive (Chetwood et al., 2019; Sheikh et al., 2019). In low-income settings, research priorities related to nitrosamine-ESCC carcinogenicity could focus on understanding the risk associated with excess intake of preformed exogenous nitrosamines as they relate to common lifestyle and dietary habits for most SSA communities.

Acetaldehyde Acetaldehyde is a primary metabolite of ethanol and is metabolised by alcohol dehydrogenases (ADH) in the liver. Subsequent oxidation of acetaldehyde to a less toxic metabolite, acetate, is achieved by acetate dehydrogenase (ALDH). Genetic polymorphism in ADH and ALDH were correlated with ESCC incidence in Asia ( Tanaka et al., 2010; Wu et al., 2012), suggesting acetaldehyde’s role or its metabolites in ESSC pathogenesis. Similarly, in a high ESCC region of western Kenya (Nieminen et al., 2013), a common traditional fermented drink was shown to produce high levels of acetaldehyde (>100 umol/L), which is a possible human carcinogen (IARC, 1999).

Mycotoxins* Mycotoxins are secondary metabolites produced by filamentous fungi (Kharayat and Singh, 2018). Some foodborne mycotoxins are annotated as carcinogenic to humans such as AFs – promoting hepatocellular cancer ( Claeys et al., 2020; Henry et al., 2002), and some evidence suggesting FUMs as ESCC risk factor (Marasas, 1981). AFs are produced by Aspergillus spp. and affect maize and groundnuts (Sirma et al., 2018). The dietary content of AFs is worrisome, considering that maize is a typical staple food among many communities in SSA. Exposure to AFs has been linked to acute aflatoxicosis and hepatocellular carcinoma (Serck-Hanssen, 1970; WHO and JECFA, 2017). AFB1 interferes with vitamins (A, D, B12) and minerals (selenium and zinc, Table S1). Indeed, selenium and zinc deficiencies have been associated with ESCC risk (Abnet et al., 2005a; Cai et al., 2016). To date, there has been no direct assessment of AFs on ESCC risk in SSA, indicating a need for appropriately designed individual-level studies. Further, the possibility that AFs contribute to ESCC in East Africa in the presence of gene/environment-environment interactions remains unknown. FUMs are produced by Fusarium species (Smith, 2018). Increased ESCC incidence was reported in high maize cultivation areas and was associated with FUMs contamination (Marasas, 1981). FUMs levels were 20-times higher in high ESCC incidence areas, possibly suggesting a functional role of FUMs in ESCC-tumorigenesis. Similar trends have been reported in China and Iran (Chu and Li, 1994; Shephard et al., 2000), but these observations were ecological and lacked strong individual-level evidence

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day), i.e. RR 6.0, 95% CI: 3.2–11.0 and RR 3.3, 95% CI: 2.0–5.5, respectively. In contrast, Sewram and colleagues (Sewram et al., 2016) showed no difference in ESCC risk between frequent smokers (≥seven cigarettes/day) and less-frequent (<four cigarettes/day) smokers (RR 3.14, 95% CI: 1.09–9.07 and RR 3.47, 95% CI: 1.99–6.04, respectively). Irrespective, increasing tobacco usage could result in the cumulative effects of PAHs (Table 2), i.e. benzo[a] pyrene and aromatic amines, i.e. 4-aminobiphenyl, which are well-known human carcino-gens (IARC, 2010a, 2010b).

3.3. Dietary factors

Ecological analysis of seven micronutrients across Africa (Schaafsma et al., 2015) has shown an inverse relationship between dietary selenium and ESSC incidence rates. Moreover, a pooled analysis (Cai et al., 2016) involving prospective cohort studies from the Netherlands and China demonstrated an inverse relationship between ESCC risk and toenail selenium (RR 0.37, 95% CI: 0.16–0.86) as well as dietary selenium (RR 0.48, 95% CI:0.25–0.89), Table S1. The protective effect of selenium in ESCC pathogenesis could be related to its antioxidant and cell cycle regulation properties (Jackson and Combs, 2008). According to expert’s opinion, the recommended selenium dietary intake is between 25 and 75 μg per day per person (Fairweather-Tait et al., 2011; Hurst et al., 2013). Irrespective of selenium species, soil type, food supplementation, and fortification (Fig. 3e), the primary dietary sources of selenium are bread, cereals, offal, marine fish, eggs, and dairy products (Fairweather- Tait et al., 2011), Fig. 3f–i.

There is accumulating evidence that supports the protective effects of

Abbreviations: PAHs, Polycyclic Aromatic Hydrocarbons; Alcohol De-hydrogenases (ADH); Acetate Dehydrogenase (ALDH); Oesophageal Squamous Cell Carcinoma (ESCC); Aflatoxins (AFs); Fumonisins (FUMs); sub-Saharan Af-rica (SSA).

* or needing further research.

Fig. 3. ESCC risk mitigation strategies: a. Some African countries like Tanzania have banned selling and consuming cheap alcoholic drinks in plastic drinks to control use among minors (AfricaNews, 2017). b. Following the WHO framework convention on tobacco control (WHO FCTC), some African countries, including Kenya, have enacted tobacco control legislative measures to help reduce tobacco use by the public (ITC, 2021). c. To reduce household air pollution, recent findings in developing settings have supported the use of improved cookstoves (chitetezo mbaula) with less use of biomass fuel (Jagger et al., 2017). d. Adequate intake of fruits and vegetables may lower the risk of developing ESSC (Sewram et al., 2014) The actual protective mechanism is obscure, but some evidence suggests the role of an-tioxidants (Miller and Snyder, 2012). e. Selenium has potential protective effects against ESCC risk and appears low in some countries of the African EC corridor (Schaafsma et al., 2015) The bioavailability of selenium in crops and eventually in humans is affected by soil type (Hurst et al., 2013) Soils may be enriched with selenium by applying fertilizers fortified with selenium. f - i: Some of the typical dietary sources of selenium include marine fish, hen eggs, bread, and offals, respectively (Fairweather-Tait et al., 2011).

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fruits and vegetables (Fig. 3d) in ESCC tumorigenesis (Table 1). In a multi-centre hospital-based case-control study in South Africa comprising 670 ESCC cases and 1188 controls (Sewram et al., 2014), regular consumption of green leafy vegetables was shown to be more protective against ESCC risk. In comparison to individuals eating ≤ one green leafy vegetable per week, males consuming green leafy vegetables ≥ five days per week had 38% ESCC reduced risk (RR 0.62, 95% CI: 0.38–0.99), while females had 50% reduced odds (RR 0.50, 95% CI: 0.30–0.84) at the same level of consumption. Similarly, compared with those eating fruits ≤ one day per week, males taking fruits ≥ five days per week had a 49% reduced ESCC risk (RR 0.51, 95% CI: 0.32–0.81), while females had 58% ESCC reduced risk. The mechanism for EC pro-tective function in high green leafy vegetables and fruit consumers re-mains elusive, although some leads could suggest antioxidant effects of phytochemicals (Miller and Snyder, 2012). Indeed, if antioxidants play an essential role in ESCC pathogenesis, then caution must be exercised when preparing food. For instance, a Nigerian study showed decreased levels of vitamin C, a potent antioxidant, from boiling tropical leafy vegetables (Adefegha and Oboh, 2011). In terms of the contribution of micronutrients to the ESCC burden in SSA, whilst a role is certainly plausible and likely, research gaps remain and are challenging to over-come in the context of the predominant study design (case-control studies) where biomarker-based assessments are prone to reverse cau-sality due to severe dysphagia in ESCC patients.

Processed red meat may convey high ESSC risk. Although there is a paucity of data on ESCC risk associating with processed red meat con-sumption in SSA, smoke heating (Fig. 2d) is a common food preparation or preservation practice in many African communities (Ledesma et al., 2016). Smoke heating involves smouldering of food (i.e., meat) on the grill over smoke. Among high red meat consumers, like in South Africa, this might be a vital ESCC risk factor. The increased ESCC risk associated with red meat may be explained by the production of heterocyclic amines (HCAs), and PAHs produced during the smouldering process (Hemeryck and Vanhaecke, 2016). Both PAHs and HCAs have been associated with gastrointestinal tract tumorigenesis (Cross et al., 2011). Another possible mechanism of red meat-induced carcinogenesis in-cludes the formation of oxidative and alkylating DNA adducts from heme iron products, N-nitroso compounds, and lipid peroxides (Hem-eryck et al., 2018).

3.4. Biomass smoke

Smoke from solid fuel (Biomass) is a well-established risk factor for lung cancer (Dean et al., 2010), while the evidence against ESCC risk is limited.

In SSA, exposure to biomass smoke is more likely to emanate from firewood and charcoal (Fig. 2c). A significant proportion of households in low-income settings either do not have access or do not afford expensive non-solid fuel sources (i.e. electricity or gas) thus are compelled to use cheap cooking sources, i.e. solid biomass fuels (Kayamba et al., 2017). However, solid biomass smoke contains com-pounds that may induce various cancers, including ESCC (IARC, 2010c). For instance, in case-control studies in Kenya (Patel et al., 2013), Malawi (Mlombe et al., 2015), and Zambia (Kayamba et al., 2015), the use of charcoal and firewood were positively associated with increased ESCC risk (Table 1). Moreover, in a pooled analysis of case-control studies in Africa (Okello et al., 2019), Okello and colleagues demonstrated a strong association between biomass smoke exposure and ESCC risk (RR 3.35, 95% CI: 2.34–4.80, heterogeneity I2 = 73.4%). However, research questions remain on precise ESCC risk quantification by biomass fuel type and exposure intensity. Previous studies have had limited exposure intensity data and weak exposure contrasts due to wood being such a dominant fuel type and women almost exclusively performing cooking roles.

The mechanisms in biomass smoke-induced ESSC tumorigenesis are not clearly defined. However, some evidence suggests high-level PAH

exposure during wood-burning (Table 2) and subsequent DNA damage (IARC, 2010a, 2010c). Indeed a community-based surveillance study on indoor use of wood and carcinogenic exposure in Kenya (Mwachiro et al., 2021) has illustrated a positive association between PAH exposure and increased risk of oesophageal dysplasia, ESCC precursor lesion, among female non-smokers.

3.5. Unpiped water

Unpiped water (Fig. 2g) is a potential route for different chemical carcinogens (Sheikh et al., 2019). While the WHO Progress report on Household Drinking Water, Sanitation and Hygiene 2000–2017 (WHO, 2019) indicated usage of unpiped water for over 60% of households in the entire population of SSA, little effort has been made to identify po-tential contaminants of unpiped water in this region. In a case-control study in Kenya (Menya et al., 2019b), individuals drinking water from the well and spring (or river) showed higher ESCC risk (RR 1.7, 95% CI: 0.9–3.2 and RR 2.9, 95% CI: 1.5–5.7, respectively) compared to in-dividuals consuming piped water (Table 1). Visual examination showed a geographical co-location between high ESCC incidence regions and high groundwater fluoride levels. While there is no evidence to suggest carcinogenicity of fluoride in human cancers, studies of water quality and dental fluorosis (in the context of oral health more generally) are needed as previously reported associations suffered greatly from misclassification (false positives) (Menya et al., 2019b; Mmbaga et al., 2021a). Observational data suggest a close connection between the high nitrate content in unpiped water sources and ESCC risk (Keshavarzi et al., 2012) – pertinent individual-level studies are needed in SSA. The possible mechanism in nitrate-initiated tumorigenesis may be through the formation of endogenous nitrosamines (Table 2).

3.6. Hot food and beverages

Consumption of hot drinks such as tea (Fig. 2f), coffee, mate, and hot food (Fig. 2a) in general, has been associated with increased ESCC risk in SSA and elsewhere (Table 1 and S1). For instance, in a hospital case- control study in eastern Africa (Middleton et al., 2019), involving 430 cases and 440 controls, the odds of developing ESCC increased by 3.7- fold (RR 3.66, 95% CI: 2.10–6.50) and 1.4-fold (RR 1.40, 95% CI: 0.97–2.73) in drinkers of ‘very hot’ and ‘hot’ tea respectively relative to ‘warm tea’. Most of the participants consumed an average of three cups of tea (approximately 750 mL) per day. Similarly, in the same region (Patel et al., 2013), a case-control study of 150 ESCC cases and 150 controls showed increased ESCC risk in individuals taking hot tea than controls (RR 12.78, 95% CI: 6.98–23). Again, in a case-control study in Ethiopia (Deybasso et al., 2021), the odds of developing ESCC were more likely for individuals consuming very hot than hot porridge (RR 3.1, 95% CI: 1.38–7.03). Although these associations are based on self- reported temperatures, studies in Iran have demonstrated that self- reported drinking temperature is a reliable measure of the habitual thermal injury (Sheikh et al., 2019) because a single measurement of drinking temperature at first sip does not capture both dimensions of heat exposure - temperature and sip volume - across all sips in a beverage drinking episode. Outside Africa (Table S1), taking large amounts of hot tea has also been positively associated with ESCC risk. In a cohort study in Iran (Sheikh et al., 2019), daily intakes of more than six cups of hot tea (≥60 ◦C) were significantly associated with increased ESCC risk (RR 1.60, 95% CI: 1.15–2.22) in a fully adjusted model.

Several thermal mechanisms have been implicated in ESCC tumori-genesis. It is reported that thermal injury may induce inflammatory and intracellular signalling responses that may form mutant cell lines (Maghsudlu and Yazd, 2017). Another possible explanation is the direct permeation of carcinogens facilitated by thermal insults that may be a stimulus for aberrant oesophageal squamous cell proliferation. A further possibility is the indirect contamination of hot beverages with carcino-gens. For example, Lin and Zhu demonstrated accumulation of PAHs in

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black tea (Total PAHs = 9650 ± 1200 µg/kg) during the manufacturing process (Lin and Zhu, 2004). Nonetheless, Mwachiro and colleagues did not find a significant concentration of PAHs in commercial purchased tea leaves (<0.3 µg/kg of leaves) (Mwachiro et al., 2019) – probably reflecting differences in the processing procedures and contamination of PAHs from atmospheric precipitation from industrial air pollution.

3.7. Poor oral health

Poor oral health, including teeth loss, dental fluorosis, teeth decay, and the frequency of teeth brushing, is associated with increased ESCC risk (Table 1). In a case-control study in Tanzania (Mmbaga et al., 2021a), involving 310 cases and 313 control, ESCC risk increased line-arly among individuals with high DMFT index (i.e. tooth decay +missing teeth + filled tooth), RR 3.3, 95% CI: 1.8–6.0 for DMFT index ≥10 versus 0. In another case-control study in Kenya (Menya et al., 2019b), involving 430 ESCC cases and 440 controls, significant positive associations were established observed between the decay of more than three teeth (RR 8.8, 95% CI: 4.9–15.8) and ESCC risk. Toothbrush type (mswaki: Arak tree stick), missing teeth (at least two), and oral leuco-plakia were also reported as important ESCC determinants alongside drinking spring or river water. While regular teeth brushing has been associated with decreased chances for developing ESCC in other parts of the world (Chen et al., 2015), Table S1, data for teeth brushing practices is only emerging in SSA. In East Africa (Menya et al., 2019b), infrequent tooth brushing (i.e. washing teeth once per week) was associated with increased ESCC risk (RR 2.3, 95% CI: 1.0–5.5) in comparison to daily teeth brushing.

A tenacious proliferating signal in living cells is one of the cancer hallmarks (Hanahan and Weinberg, 2011). Poor oral health, as marked by teeth decay and periodontal disease, could lead to ESCC tumorigen-esis by inducing periodontitis (a persistent low-grade inflammation) and promoting a pro-carcinogenic oral and oesophageal microbiome, for which relevant studies are underway. Similarly, incomplete chewing and swallowing of large particles due to teeth loss may cause continuous irritation of oesophageal mucosa (Abnet et al., 2005b). Aside from persisted inflammation from periodontitis, metabolites from periodontal pathogens may be genotoxic and may increase gastrointestinal cancer risk (ESCC inclusive).

4. Human papilloma virus and other viral infections

Human papillomavirus (HPV) has been defined as an established determinant for anal, cervix, vagina, and oropharynx cancer (Doorbar et al., 2012). In the IARC monograph 100b (IARC, 2012), the working group reviewed the evidence of HPV in ESCC and concluded that the results were either inadequate or inconsistent. Ideally, HPV serological markers are measured to represent long-term exposure. However, in one such study, the Interscope study (Sitas et al., 2012), no significant serological evidence of HPV’s role in ESCC pathogenesis was found, as the anticipated high-risk HPV subtypes (i.e. HPV 16 and 18) were only present in less than 3% of cases. Although the role of high-risk HPV-type 16 in ESCC tumorigenesis might be suggestive of its high tropism for basal cells of stratified squamous endothelium (Geßner et al., 2018); genomic characterisation studies conducted by Cancer Genome Atlas Research (TCGA) programme could not establish detectable levels of HPV mRNA transcripts in ESCC tissue (Kim et al., 2017).

Viral infections account for over 16% of all malignant tumours (Chang et al., 2017; Parkin et al., 2006; Plummer et al., 2016). For instance, in Zambia (Kayamba et al., 2015), HIV seropositivity was associated with increased ESCC risk in age-sex matched controls. In contrast, a recent case-control study in the same setting could not establish a relation between ESCC risk and HIV serostatus or other viral infections, i.e. HPV, varicella-zoster virus, herpes simplex virus, cyto-megalovirus, or Epstein–Barr virus (Geßner et al., 2021). Thus, while viral onco-modulatory properties may be attributed to cell tropism, the

cancer outcome is seemingly a function of several host-pathogen in-teractions (Chang et al., 2017). In this regard, the role of viruses in ESCC tumorigenesis should carefully be interpreted in the face of confounding and reverse causality.

5. ESCC epigenetic factors (endogenous biological responses)

The common molecular alterations in ESCC tumorigenesis include single nucleotide polymorphisms, gene amplification, and promoter hypermethylation (Talukdar et al., 2021; Yang and Chen, 2020). We discuss genome-wide association studies (GWAS), gene susceptibility studies, and methylome studies on ESCC predisposition in Africa and relate findings to relevant studies conducted elsewhere.

Frequently altered genes in ESCC tumorigenesis include those with the function of transcription, xenobiotics metabolising, DNA repair, and cell-cycle regulation (Talukdar et al., 2018). In an integrated genomic characterisation of oesophageal carcinomas in western and eastern populations, the TCGA programme identified significant genetic muta-tions or amplification or inactivation of NRF2, SOX2, TP63, NOTCH1, ZNF750, CDK6, KDM2D, PIK3R1, and TP53 genes (Kim et al., 2017) in ESCC tumorigenesis. The implicated genes could be linked to ESCC tumorigenesis since they function to regulate oxidative stress, i.e. NRF2 (Shibata et al., 2011), gene expression, i.e. TP53 (Olivier et al., 2004), cell differentiation, i.e. NOTCH1, ZNF750, TP63, SOX 2 (Kim et al., 2017), chromatin modelling, i.e. KDM2D (D’Oto et al., 2016), and cell- cycle regulation, i.e. CDK6, and PIK3R1 (Kim et al., 2017; Nebenfuehr et al., 2020). In contrast, pooled analyses of Africa studies have identi-fied variants in ADH3, ALDH2, AR, CASP8, COX-2, TP53, RUNX1, CHEK2, MGMT, MLH3, MSH3, PMS1, and CYP2E1 loci to be important ESCC predisposing factors (Bye et al., 2012, 2011; Chen et al., 2019; Dietzsch et al., 2003; Li et al., 2008; Simba et al., 2019; Vogelsang et al., 2014, 2012), Table 2. The differences in the susceptibility loci in the African population (Table 2) versus the Western and Eastern populations (Kim et al., 2017) could explain differences in external exposures in these geographical settings that may also influence diverse genetic predisposition to ESCC.

On the other hand, epigenetic studies show alterations of the human epigenome from early human life stages (Herceg et al., 2018). External exposures may alter the human epigenome and predispose individuals to cancers. The common epigenetic changes of human DNA involve methylation of cytosine-guanine dinucleotides regions, CpG islands (Talukdar et al., 2018). CpG hypermethylation in gene promoter regions typically results in transcription silencing, while hypomethylation may result in gene overexpression. In Southern Africa (Vogelsang et al., 2014), Table 2, methylome analysis of MSH3 promoter was an important feature for oesophageal cancer than adjacent normal tissue (P = 0.008). MSH3 methylation was significantly observed in tumours from tobacco smokers than non-smokers (RR 31.9, P = 0.031) – suggestive of cumu-lative effects of MSH3 and tobacco smoking in ESCC tumorigenesis. Indeed, a variant of MSH3 has been associated with other tobacco- related cancers, including oral squamous cell carcinoma (Mondal et al., 2013).

6. Conclusion and future perspectives

Evidence of ESCC aetiology in SSA points to important contributions of alcohol, tobacco, hot beverages, biomass fuel, and poor oral health/ hygiene in general. However, more precise risk characterisation remains necessary – while the overall role of diet, viral infections, food con-taminants and unpipped water require further clarification. Unlike lifestyle and environmental stressors, evidence of epigenetic predispo-sition to ESCC burden is limited and inconclusive except in South Africa, Table 2. More mechanistic data will be relevant to map susceptible loci across SSA.

Fortunately, most of the lifestyle and environmental stressors are modifiable or reducible. For instance, alcohol reduction and tobacco

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elimination are public health policies to be supported for the advantage of ESCC and many other non-communicable diseases. Further, biomass smoke exposure could be averted by using clean fuel energy sources; again, a poor diet could be supplemented with a regular intake of veg-etables and fruits. If mycotoxins are implicated, applying appropriate pre-and post-harvest maize process techniques such as cleaning and sorting could help mitigate human exposure to them. Moreover, dietary or soil supplementation with essential minerals such as selenium might help reduce ESCC incidence in high-risk regions. In general, in ESCC- affected SSA countries, cancer control plans can already incorporate lifestyle behavioural advice as a primary prevention strategy (Fig. 3).

As reviewed herein, the existing evidence based on ESCC aetiology in SSA has and continues to generate important information to support primary prevention. The research domain is now expanding to take full advantage of omic approaches, which could help further define a repertoire of stressors associated with ESCC risk. Such studies have commenced for the oral microbiome (Nomburg et al., 2021) and somatic mutation signatures (Moody et al., 2021) in ESCC tumour genomes, whilst African ESCC GWAS studies are underway with a South African study commenced (Chen et al., xxxx). Expansion to panels of infections and susceptible loci, metabolomics and (DNA)-adductomic approaches are also being developed by various research terms internationally. For example, the remaining uncertainty on the role of mycotoxins can be addressed using dietary specific adductomics and metabolomics, for which our present group and MYTOX-SOUTH offer our expertise and collaboration. In this fashion, a multi-disciplinary approach would bring disciplines and technologies to enhance aetiological insights. The Afri-can Esophageal Cancer Consortium, AfrECC, including the Oesophageal Squamous Cell Carcinoma African PrEvention (ESCCAPE) research, provides an appropriate platform through which such research can be performed. We envisage such multi-disciplinary collaborative initiatives will be imperative to drive regional policies to reduce ESCC burden and improve quality of life – indeed, in line with the United Nation’s Sus-tainable Development Goal 3.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work is supported by BOF 01W03419 under Ghent University, The MYTOX-SOUTH framework, Lilongwe University of Agriculture & Natural Resources, and Kamuzu University of Health Sciences (KuHES), Malawi. The authors alone are responsible for the views expressed in this review paper, which do not necessarily represent the views, decisions, or policies of the institutions with which the authors are affiliated including IARC-WHO.

MDB has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innova-tion programme (grant agreement No 946192). However, this review reflects the author’s view and the Agency is not responsible for any use that may be made of the information it contains.

Disclosure statement

The authors declare no actual or potential competing financial interests.

Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi. org/10.1016/j.envint.2021.106880.

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