Alcohol as a Non-UV Social-Environmental Risk Factor for Melanoma

Abstract

Although cancer mortality has declined among the general population, the incidence of melanoma continues to rise. While identifying high-risk cohorts with genetic risk factors improves public health initiatives and clinical care management, recognizing modifiable risk factors such as social-environmental risk factors would also affect the methods of patient outreach and education. One major modifiable social-environmental risk factor associated with melanoma is ultraviolet (UV) radiation. However, not all forms of melanoma are correlated with sun exposure or occur in sun-exposed areas. Additionally, UV exposure is rarely associated with tumor progression. Another social-environmental factor, pregnancy, does not explain the sharply increased incidence of melanoma. Recent studies have demonstrated that alcohol consumption is positively linked with an increased risk of cancers, including melanoma. This perspective review paper summarizes epidemiological data correlating melanoma incidence with alcohol consumption, describes the biochemical mechanisms of ethanol metabolism, and discusses how ethanol and ethanol metabolites contribute to human cancer, including melanoma.

Ethanol Metabolism and Melanoma

“…As most research on ethanol or AcAH concentrates on the liver and GI tract with little focus on the skin [128,129], we previously summarized their potential roles in skin biology and melanoma [9]. Similarly, despite the well-known roles of ethanol and AcAH metabolizing enzymes, there is a lack of direct evidence for their effects on melanoma.…”

“…High ethanol intake and redox imbalance in ALDH2-related mitochondrial respiration can elevate CYP2E1 levels, causing further increases in ROS levels [73,134]. Excessive ROS production has widespread impacts on cell biology, including inducing inflammation and altering signaling pathways that control cancer stem cell renewal, cell proliferation, differentiation, and angiogenesis, creating a favorable microenvironment for cancer initiation [9]. Evidence suggests that a high pro-oxidant state with impaired antioxidant defenses is related to melanocyte malignant transformation and melanoma progression [135,136].…”

“…This skin damage from ethanol is exacerbated by UV exposure, and ethanol and UV radiation can act synergistically to induce mutations and weaken protection mechanisms, including reducing melanin production and glutathione levels [138]. Ethanol and UV radiation also activate cAMP/PKA, mitogen-activated protein kinase, phos-phatidylinositol 3-kinase/protein kinase B, and Wnt/β-catenin signaling pathways, leading to altered expression of the melanocyte transcription factor microphthalmia-associated transcriptional factor (MITF) [9]. MITF regulates melanocyte biology, and its dysregulation is directly linked to melanoma development [139].…”

“…Nearly half (14 out of 29) of the studies on the relationship between alcohol consumption and melanoma, including 10 cohort and 19 case-control studies, have shown a positive correlation, while only 2 showed a negative correlation. Further, of 20 studies assessing alcohol dose effects, 13 (65%) demonstrated an association between alcohol dose and melanoma risk [9]. These associations became stronger in multiple meta-analyses with larger sample sizes [10][11][12][13].…”

“…Individual lifestyle factors associated with melanoma risk include UV exposure, cigarette smoking, alcohol use, overweight and obesity, poor diet, environmental pollution, and stress [5,6]. Recently, we summarized epidemiological data on the association between alcohol consumption and cutaneous melanoma [9]. Nearly half (14 out of 29) of the studies on the relationship between alcohol consumption and melanoma, including 10 cohort and 19 case-control studies, have shown a positive correlation, while only 2 showed a negative correlation.…”