A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer

Gormley, Mark; Dudding, Tom; Sanderson, Eleanor; Martin, Richard M.; Thomas, Steven J.; Tyrrell, Jessica; Ness, Andy R; Brennan, Paul; Munafò, Marcus R.; Pring, Miranda; Boccia, Stefania; Olshan, Andrew F.; Diergaarde, Brenda; Hung, Rayjean J.; Liu, Geoffrey; Smith, George Davey; Richmond, Rebecca C

doi:10.1038/s41467-020-19822-6

Cited by 74 publications

(70 citation statements)

References 50 publications

(82 reference statements)

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Section: Alcohol and Cancer Riskmentioning

confidence: 99%

“…For oral and oropharyngeal cancer, an MR study using genetic data on 6000 oral or oropharyngeal cancer cases and 6600 controls found a positive causal effect of alcohol consumption independent of smoking [ 16 ]. The authors concluded that previous estimates of the association between alcohol and oral and oropharyngeal cancer from observational studies may have been underestimated [ 16 ]. Another MR study on UK Biobank data found that drinking alcohol, especially above the UK’s low-risk guideline of up to 14 units per week, was causally related with head and neck cancers, but not breast cancer [ 17 ].…”

Section: Alcohol and Cancer Riskmentioning

confidence: 99%

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Alcohol and Cancer: Epidemiology and Biological Mechanisms

et al. 2021

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Approximately 4% of cancers worldwide are caused by alcohol consumption. Drinking alcohol increases the risk of several cancer types, including cancers of the upper aerodigestive tract, liver, colorectum, and breast. In this review, we summarise the epidemiological evidence on alcohol and cancer risk and the mechanistic evidence of alcohol-mediated carcinogenesis. There are several mechanistic pathways by which the consumption of alcohol, as ethanol, is known to cause cancer, though some are still not fully understood. Ethanol’s metabolite acetaldehyde can cause DNA damage and block DNA synthesis and repair, whilst both ethanol and acetaldehyde can disrupt DNA methylation. Ethanol can also induce inflammation and oxidative stress leading to lipid peroxidation and further DNA damage. One-carbon metabolism and folate levels are also impaired by ethanol. Other known mechanisms are discussed. Further understanding of the carcinogenic properties of alcohol and its metabolites will inform future research, but there is already a need for comprehensive alcohol control and cancer prevention strategies to reduce the burden of cancer attributable to alcohol.

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Section: Alcohol and Cancer Riskmentioning

confidence: 99%

Section: Alcohol and Cancer Riskmentioning

confidence: 99%

Alcohol and Cancer: Epidemiology and Biological Mechanisms

et al. 2021

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“…Furthermore, tobacco exposure induces proinflammatory and immunosuppressive effects, which could potentially increase the likelihood of HPV infection and persistence 48,49 . Since risk factors such as smoking and alcohol consumption are strongly associated with sexual behaviour and are well established in the aetiology of HNSCC, this may confound the relationship between sexual behaviours with HPV transmission and similarly oropharyngeal cancer in observational studies 50,51 .…”

Section: Discussionmentioning

confidence: 99%

Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization

Gormley

Dudding

Kachuri

et al. 2021

Preprint

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Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. Here we evaluate aspects of sexual behaviour in relation to the risk of OPC (2,641 cases and 6,585 controls), using genetic variants associated with age at first sex (AFS) and number of sexual partners (NSP) to perform Mendelian randomization (MR) analyses. While univariable MR showed a causal effect of both later AFS and increasing NSP on OPC, results attenuated in the multivariable models (AFS IVW OR 0.7, 95%CI 0.4, 1.2, p= 0.21; NSP IVW OR 0.9, 95%CI 0.5 1.7, p= 0.76). We also found evidence for correlated pleiotropy in the genetic instruments for sexual behaviour, emphasising the need for multivariable approaches when performing MR of complex behavioural traits and the triangulation of evidence.

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“…Recently, many more variants related to alcohol use have been identified [81]. Using MR, Gormley et al confirmed that both alcohol and tobacco are independent risk factors for oral and oropharyngeal cancers with inverse variance weighted odds ratios of 2.1 and 2.6 respectively [82].…”

Section: Epidemiological Data Indicate a Strong Correlation Between Alcohol And Oral Malignanciesmentioning

confidence: 99%

Ethanol-Induced Cell Damage Can Result in the Development of Oral Tumors

Hoes

Dok

Verstrepen

et al. 2021

Cancers

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Alcohol consumption is an underestimated risk factor for the development of precancerous lesions in the oral cavity. Although alcohol is a well-accepted recreational drug, 26.4% of all lip and oral cavity cancers worldwide are related to heavy drinking. Molecular mechanisms underlying this carcinogenic effect of ethanol are still under investigation. An important damaging effect comes from the first metabolite of ethanol, being acetaldehyde. Concentrations of acetaldehyde detected in the oral cavity are relatively high due to the metabolization of ethanol by oral microbes. Acetaldehyde can directly damage the DNA by the formation of mutagenic DNA adducts and interstrand crosslinks. Additionally, ethanol is known to affect epigenetic methylation and acetylation patterns, which are important regulators of gene expression. Ethanol-induced hypomethylation can activate the expression of oncogenes which subsequently can result in malignant transformation. The recent identification of ethanol-related mutational signatures emphasizes the role of acetaldehyde in alcohol-associated carcinogenesis. However, not all signatures associated with alcohol intake also relate to acetaldehyde. This finding highlights that there might be other effects of ethanol yet to be discovered.

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A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer

Cited by 74 publications

References 50 publications

Alcohol and Cancer: Epidemiology and Biological Mechanisms

Alcohol and Cancer: Epidemiology and Biological Mechanisms

Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization

Ethanol-Induced Cell Damage Can Result in the Development of Oral Tumors

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