Dietary nutrient intake, ethnicity, and epigenetic silencing of lung cancer genes detected in sputum in New Mexican smokers

Lung cancer (LC) gene methylation detected in sputum assesses field cancerization and predicts LC incidence. Hispanic smokers have higher LC susceptibility compared to non-Hispanic Whites (NHW). We aimed to identify novel dietary nutrients affecting LC gene methylation and determine the degree of ethnic disparity in methylation explained by diet. Dietary intakes of 139 nutrients were assessed using a validated Harvard food frequency questionnaire in 327 Hispanics and 1502 NHWs from the Lovelace Smokers cohort (LSC). Promoter methylation of twelve LC genes was assessed in sputum DNA. A global association was identified between dietary intake and gene methylation (Ppermutation=0.003). Seventeen nutrient measurements were identified with magnitude of association with methylation greater than that seen for folate. A stepwise approach identified B12, manganese, sodium, and saturated fat as the minimally correlated set of nutrients whose optimal intakes could reduce the methylation by 36% (Ppermutation<0.001). Six protective nutrients included vitamin D, B12, manganese, magnesium, niacin, and folate. Approximately 42% of ethnic disparity in methylation was explained by insufficient intake of protective nutrients in Hispanics compared to NHWs. Functional validation of protective nutrients showed an enhanced DNA repair capacity towards double-strand DNA breaks, a mechanistic biomarker strongly linked to acquisition of LC gene methylation in smokers. Dietary intake is a major modifiable factor for preventing promoter methylation of LC genes in smokers' lungs. Complex dietary supplements could be developed based on these protective nutrients for LC chemoprevention in smokers. Hispanic smokers may benefit the most from this complex for reducing their LC susceptibility.

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