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Oesophageal cancer (OC) in South Africa remains a major public health problem with enormous variation in incidence and geographical distribution suggesting that the influence of an environmental factor or cluster of factors that is region specific may be at play.The former Transkei region of the Eastern Cape Province of South Africa reports one of the highest incidence rates of OC in the country and is one of three hotspot regions of the world for this disease.Despite treatment advances, this aggressive malignancy commonly presents at an advanced stage with a poor prognosis.A multicentre case-control study was undertaken at three of the major referral hospitals in the Province where patients were interviewed using a structured questionnaire to obtain information on tobacco usage, alcohol consumption, dietary preferences relating to a traditional Xhosa diet, and the use of wild plants for dietary and medicinal purposes..Data from patients comprising 670 incident cases of squamous cell carcinoma of the oesophagus and 1188 controls were analysed using unconditional multiple logistic-regression models to estimate odds ratios (ORs) after adjustment for various confounders including age, hospital, years of education and residence.Tobacco smoking, alcohol consumption and the consumption of wild plants (imifino) were significantly associated with OC risk in both males and females.Principal component factoranalysis revealed three distinct dietary patterns.Dietary pattern 1, comprising sorghum,green leafy and podded vegetables, fruits and meat was observed to confer protective effects (OR=0.54, 95% CI 0.34-0.89).Dietary pattern 2, comprising maize, imifino and beans was associated with an increased risk (OR=1.67, 95%CI 1.04-2.67) whilstdietary pattern 3, comprising exclusively of wheat-based products was observed to confer protective effects.Of the 19 plants used as dietary supplements, 6 were associated with a significant increase in OC risk (OR=1.04-4.12).Similarly, of the 38 medicinal plants investigated, 4 were associated with a significant risk of developing OC (OR=1.41-2.22).These plants were further evaluated for mutagenicity, trace element levels and mycotoxin contamination.Whilst the mycotoxin levels in these plants were similar to background levels found in maize, some plants displayed mutagenicity through frameshift DNA mutations, base-pair substitutions and oxidative cell damage.This study revealed that in addition to tobacco smoking, alcohol drinking, and the consumption of diets low in fruits and vegetables, the use of certain dietary and medicinal wild plants are positively associated with OC in this population and is further supported by mechanistic evidence.