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Alcohol and smoking habits in association with hepatocellular carcinoma risk

Aglago, Elom K. ; Ramos, Ines ; Keski-Rahkonen, Pekka ; Chatziioannou, Chrysovalantou ; Freisling, Heinz ; Fedirko, Veronika ; Gunter, Marc J. ; Dahm, Christina C. ; Langmann, Fie and Bondonno, Nicola , et al. (2025) In International Journal of Cancer 157(4). p.644-657
Abstract

We assessed hepatocellular carcinoma (HCC) risk associated with smoking and alcohol consumption and their interactions, using both questionnaire data and objective serum biomarkers. Information on smoking and alcohol consumption was collected at baseline from 450,112 participants of the EPIC cohort, among whom 255 developed HCC after a median follow-up of 14 years. In a nested case–control subset of 108 HCC cases and 108 matched controls, known biomarkers of smoking (cotinine, nicotine) and habitual alcohol consumption (2-hydroxy-3-methylbutyric acid) were annotated from untargeted metabolomics features. Multivariable-adjusted hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were computed, and multiplicative... (More)

We assessed hepatocellular carcinoma (HCC) risk associated with smoking and alcohol consumption and their interactions, using both questionnaire data and objective serum biomarkers. Information on smoking and alcohol consumption was collected at baseline from 450,112 participants of the EPIC cohort, among whom 255 developed HCC after a median follow-up of 14 years. In a nested case–control subset of 108 HCC cases and 108 matched controls, known biomarkers of smoking (cotinine, nicotine) and habitual alcohol consumption (2-hydroxy-3-methylbutyric acid) were annotated from untargeted metabolomics features. Multivariable-adjusted hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were computed, and multiplicative and additive interaction parameters were calculated. Compared to never smokers, current smokers had a higher HCC risk (HR = 2.46, 95% CI = 1.77–3.43) dose-dependently with the number of cigarettes smoked per day (Ptrend <.001). Compared to light drinkers, HCC risk was higher in former (HR = 3.20, 95% CI = 1.70–6.03), periodically heavy (HR = 1.98, 95% CI = 1.11–3.54), and always heavy (HR = 5.51, 95% CI = 2.39–12.7) drinkers. Higher HCC risk was also observed in the highest versus the lowest tertiles of cotinine (OR = 4.88, 95% CI = 1.52–15.70), nicotine (OR = 5.80, 95% CI = 1.33–25.30) and 2-hydroxy-3-methylbutyric acid (OR = 5.89, 95% CI = 1.33–26.12). Questionnaire-assessed smoking and alcohol exposures did not demonstrate an HCC risk interaction at the multiplicative (MI = 0.88, 95% CI = 0.40–1.96) or additive (RERI = 0.71, 95% CI = −10.1 to 23.6; attributable proportion = 0.17, 95% CI = −0.52 to 1.16; synergy index = 1.27, 95% CI = 0.98–1.66) scales. Similar analyses with cotinine, nicotine, and 2-hydroxy-3-methylbutyric acid also did not show interactions between smoking and alcohol consumption on HCC risk. Smoking and alcohol consumption are strong independent risk factors for HCC and do not appear to synergistically impact its risk, but larger studies are needed.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biological markers, ethanol, interaction, liver cancer, tobacco
in
International Journal of Cancer
volume
157
issue
4
pages
14 pages
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105000825625
  • pmid:40098437
ISSN
0020-7136
DOI
10.1002/ijc.35401
language
English
LU publication?
yes
id
1556a8bd-fc5f-4233-a507-b26252942dca
date added to LUP
2025-09-12 12:34:52
date last changed
2025-09-12 12:48:20
@article{1556a8bd-fc5f-4233-a507-b26252942dca,
  abstract     = {{<p>We assessed hepatocellular carcinoma (HCC) risk associated with smoking and alcohol consumption and their interactions, using both questionnaire data and objective serum biomarkers. Information on smoking and alcohol consumption was collected at baseline from 450,112 participants of the EPIC cohort, among whom 255 developed HCC after a median follow-up of 14 years. In a nested case–control subset of 108 HCC cases and 108 matched controls, known biomarkers of smoking (cotinine, nicotine) and habitual alcohol consumption (2-hydroxy-3-methylbutyric acid) were annotated from untargeted metabolomics features. Multivariable-adjusted hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were computed, and multiplicative and additive interaction parameters were calculated. Compared to never smokers, current smokers had a higher HCC risk (HR = 2.46, 95% CI = 1.77–3.43) dose-dependently with the number of cigarettes smoked per day (P<sub>trend</sub> &lt;.001). Compared to light drinkers, HCC risk was higher in former (HR = 3.20, 95% CI = 1.70–6.03), periodically heavy (HR = 1.98, 95% CI = 1.11–3.54), and always heavy (HR = 5.51, 95% CI = 2.39–12.7) drinkers. Higher HCC risk was also observed in the highest versus the lowest tertiles of cotinine (OR = 4.88, 95% CI = 1.52–15.70), nicotine (OR = 5.80, 95% CI = 1.33–25.30) and 2-hydroxy-3-methylbutyric acid (OR = 5.89, 95% CI = 1.33–26.12). Questionnaire-assessed smoking and alcohol exposures did not demonstrate an HCC risk interaction at the multiplicative (MI = 0.88, 95% CI = 0.40–1.96) or additive (RERI = 0.71, 95% CI = −10.1 to 23.6; attributable proportion = 0.17, 95% CI = −0.52 to 1.16; synergy index = 1.27, 95% CI = 0.98–1.66) scales. Similar analyses with cotinine, nicotine, and 2-hydroxy-3-methylbutyric acid also did not show interactions between smoking and alcohol consumption on HCC risk. Smoking and alcohol consumption are strong independent risk factors for HCC and do not appear to synergistically impact its risk, but larger studies are needed.</p>}},
  author       = {{Aglago, Elom K. and Ramos, Ines and Keski-Rahkonen, Pekka and Chatziioannou, Chrysovalantou and Freisling, Heinz and Fedirko, Veronika and Gunter, Marc J. and Dahm, Christina C. and Langmann, Fie and Bondonno, Nicola and Tjønneland, Anne and Severi, Gianluca and Truong, Therese and Katzke, Verena and Kaaks, Rudolf and Bergmann, Manuela and Schulze, Matthias B. and Masala, Giovanna and Pala, Valeria and de Magistris, Maria Santucci and Di Girolamo, Chiara and Lukic, Marko and Gram, Inger Torhild and Bonet, Catalina and Sánchez, Maria Jose and Chirlaque, María Dolores and Amiano, Pilar and Guevara, Marcela and Vermeulen, Roel and Manjer, Jonas and Eriksson, Linda and Key, Tim J. and Mayen, Ana Lucia and Dossus, Laure and Weiderpass, Elisabete and Heath, Alicia K. and Ferrari, Pietro and Jenab, Mazda}},
  issn         = {{0020-7136}},
  keywords     = {{biological markers; ethanol; interaction; liver cancer; tobacco}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{644--657}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{International Journal of Cancer}},
  title        = {{Alcohol and smoking habits in association with hepatocellular carcinoma risk}},
  url          = {{http://dx.doi.org/10.1002/ijc.35401}},
  doi          = {{10.1002/ijc.35401}},
  volume       = {{157}},
  year         = {{2025}},
}