Alcohol and smoking habits in association with hepatocellular carcinoma risk

Elom K Aglago; Ines Ramos; Pekka Keski-Rahkonen; Chrysovalantou Chatziioannou; Heinz Freisling; Veronika Fedirko; Marc J Gunter; Christina C Dahm; Fie Langmann; Nicola Bondonno; Anne Tjønneland; Gianluca Severi; Therese Truong; Verena Katzke; Rudolf Kaaks; Manuela Bergmann; Matthias B Schulze; Giovanna Masala; Valeria Pala; Maria Santucci de Magistris; Chiara Di Girolamo; Marko Lukic; Inger Torhild Gram; Catalina Bonet; Maria-Jose Sánchez; María-Dolores Chirlaque; Pilar Amiano; Marcela Guevara; Roel Vermeulen; Jonas Manjer; Linda Eriksson; Tim J Key; Ana-Lucia Mayen; Laure Dossus; Elisabete Weiderpass; Alicia K Heath; Pietro Ferrari; Mazda Jenab

doi:10.1002/ijc.35401

Alcohol and smoking habits in association with hepatocellular carcinoma risk

Elom K Aglago
, Ines Ramos
, Pekka Keski-Rahkonen
, Chrysovalantou Chatziioannou
, Heinz Freisling
, Veronika Fedirko
, Marc J Gunter
, Christina C Dahm
, Fie Langmann
, Nicola Bondonno
, Anne Tjønneland
, Gianluca Severi
, Therese Truong
, Verena Katzke
, Rudolf Kaaks
, Manuela Bergmann
, Matthias B Schulze
, Giovanna Masala
, Valeria Pala
, Maria Santucci de Magistris

Chiara Di Girolamo, Marko Lukic, Inger Torhild Gram, Catalina Bonet, Maria-Jose Sánchez, María-Dolores Chirlaque, Pilar Amiano, Marcela Guevara, Roel Vermeulen, Jonas Manjer, Linda Eriksson, Tim J Key, Ana-Lucia Mayen, Laure Dossus, Elisabete Weiderpass, Alicia K Heath, Pietro Ferrari, Mazda Jenab

Research output: Contribution to journal › Article › Academic › peer-review

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 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 trend <.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.

Original language	English
Pages (from-to)	644-657
Number of pages	14
Journal	International Journal of Cancer
Volume	157
Issue number	4
Early online date	18 Mar 2025
DOIs	https://doi.org/10.1002/ijc.35401
Publication status	Published - 15 Aug 2025

Bibliographical note

Publisher Copyright:
© 2025 UICC.

Funding

The authors would like to thank the EPIC study participants and staff for their valuable contributions to this research. The authors are grateful for Ms. Nivonirina Robinot's support in conducting metabolomics laboratory analyses. We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The authors are grateful to the centers of Cambridge and Utrecht for providing their data for this study. The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

Funders	Funder number
Universitetet i Tromsø
NIHR Imperial Biomedical Research Centre
Department of Epidemiology and Biostatistics, University of California, San Francisco
Catalan Institute of Oncology
Ligue Contre le Cancer
Imperial College London
County Councils of Skåne
University of Maryland School of Public Health
Instituto de Salud Carlos III
Institut national de la santé et de la recherche médicale
Kræftens Bekæmpelse
Compagnia di San Paolo
World Cancer Research Fund
Bundesministerium für Bildung und Forschung
Cancerfonden
Centre International de Recherche sur le Cancer
Associazione Italiana per la Ricerca sul Cancro
German Institute of Human Nutrition Potsdam‐Rehbrücke
Ministerie van Volksgezondheid, Welzijn en Sport
Ministero della Salute
Institut Gustave-Roussy
ZonMw
Ministero dell’Istruzione, dell’Università e della Ricerca
Consejería de Salud y Familias, Junta de Andalucía
Deutsche Krebshilfe
Deutsches Krebsforschungszentrum
Mutuelle Générale de l'Education Nationale
Vetenskapsrådet
Agence Nationale de la Recherche	ANR‐10‐COHO‐0006
French Ministry for Higher Education	2103586016, 2102918823, 2103236497
Cancer Research UK	C8221/A29017, C864/A14136
Cancer Prevention and Research Institute of Texas	RR200056
Medical Research Council	MC‐UU_12015/1, MR/Y013662/1, MR/N003284/1, MC_UU_00006/1

Keywords

biological markers
ethanol
interaction
liver cancer
tobacco

Access to Document

10.1002/ijc.35401

Intl Journal of Cancer - 2025 - Aglago - Alcohol and smoking habits in association with hepatocellular carcinoma riskFinal published version, 1.47 MBLicence: Taverne

Cite this

Aglago, E. K., Ramos, I., Keski-Rahkonen, P., Chatziioannou, C., Freisling, H., Fedirko, V., Gunter, M. J., Dahm, C. C., Langmann, F., Bondonno, N., Tjønneland, A., Severi, G., Truong, T., Katzke, V., Kaaks, R., Bergmann, M., Schulze, M. B., Masala, G., Pala, V., ... Jenab, M. (2025). Alcohol and smoking habits in association with hepatocellular carcinoma risk. International Journal of Cancer, 157(4), 644-657. https://doi.org/10.1002/ijc.35401

@article{5dd2951e3cb24fb19881c7df8d256db0,

title = "Alcohol and smoking habits in association with hepatocellular carcinoma risk",

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 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 trend <.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. ",

keywords = "biological markers, ethanol, interaction, liver cancer, tobacco",

author = "Aglago, \{Elom K\} and Ines Ramos and Pekka Keski-Rahkonen and Chrysovalantou Chatziioannou and Heinz Freisling and Veronika Fedirko and Gunter, \{Marc J\} and Dahm, \{Christina C\} and Fie Langmann and Nicola Bondonno and Anne Tj{\o}nneland and Gianluca Severi and Therese Truong and Verena Katzke and Rudolf Kaaks and Manuela Bergmann and Schulze, \{Matthias B\} and Giovanna Masala and Valeria Pala and \{de Magistris\}, \{Maria Santucci\} and \{Di Girolamo\}, Chiara and Marko Lukic and Gram, \{Inger Torhild\} and Catalina Bonet and Maria-Jose S{\'a}nchez and Mar{\'i}a-Dolores Chirlaque and Pilar Amiano and Marcela Guevara and Roel Vermeulen and Jonas Manjer and Linda Eriksson and Key, \{Tim J\} and Ana-Lucia Mayen and Laure Dossus and Elisabete Weiderpass and Heath, \{Alicia K\} and Pietro Ferrari and Mazda Jenab",

note = "Publisher Copyright: {\textcopyright} 2025 UICC.",

year = "2025",

month = aug,

day = "15",

doi = "10.1002/ijc.35401",

language = "English",

volume = "157",

pages = "644--657",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "John Wiley and Sons Inc.",

number = "4",

}

Aglago, EK, Ramos, I, Keski-Rahkonen, P, Chatziioannou, C, Freisling, H, Fedirko, V, Gunter, MJ, Dahm, CC, Langmann, F, Bondonno, N, Tjønneland, A, Severi, G, Truong, T, Katzke, V, Kaaks, R, Bergmann, M, Schulze, MB, Masala, G, Pala, V, de Magistris, MS, Di Girolamo, C, Lukic, M, Gram, IT, Bonet, C, Sánchez, M-J, Chirlaque, M-D, Amiano, P, Guevara, M, Vermeulen, R, Manjer, J, Eriksson, L, Key, TJ, Mayen, A-L, Dossus, L, Weiderpass, E, Heath, AK, Ferrari, P & Jenab, M 2025, 'Alcohol and smoking habits in association with hepatocellular carcinoma risk', International Journal of Cancer, vol. 157, no. 4, pp. 644-657. https://doi.org/10.1002/ijc.35401

TY - JOUR

T1 - Alcohol and smoking habits in association with hepatocellular carcinoma risk

AU - Aglago, Elom K

AU - Ramos, Ines

AU - Keski-Rahkonen, Pekka

AU - Chatziioannou, Chrysovalantou

AU - Freisling, Heinz

AU - Fedirko, Veronika

AU - Gunter, Marc J

AU - Dahm, Christina C

AU - Langmann, Fie

AU - Bondonno, Nicola

AU - Tjønneland, Anne

AU - Severi, Gianluca

AU - Truong, Therese

AU - Katzke, Verena

AU - Kaaks, Rudolf

AU - Bergmann, Manuela

AU - Schulze, Matthias B

AU - Masala, Giovanna

AU - Pala, Valeria

AU - de Magistris, Maria Santucci

AU - Di Girolamo, Chiara

AU - Lukic, Marko

AU - Gram, Inger Torhild

AU - Bonet, Catalina

AU - Sánchez, Maria-Jose

AU - Chirlaque, María-Dolores

AU - Amiano, Pilar

AU - Guevara, Marcela

AU - Vermeulen, Roel

AU - Manjer, Jonas

AU - Eriksson, Linda

AU - Key, Tim J

AU - Mayen, Ana-Lucia

AU - Dossus, Laure

AU - Weiderpass, Elisabete

AU - Heath, Alicia K

AU - Ferrari, Pietro

AU - Jenab, Mazda

PY - 2025/8/15

Y1 - 2025/8/15

N2 - 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 trend <.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.

AB - 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 trend <.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.

KW - biological markers

KW - ethanol

KW - interaction

KW - liver cancer

KW - tobacco

UR - https://www.scopus.com/pages/publications/105000825625

U2 - 10.1002/ijc.35401

DO - 10.1002/ijc.35401

M3 - Article

C2 - 40098437

SN - 0020-7136

VL - 157

SP - 644

EP - 657

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 4

ER -

Alcohol and smoking habits in association with hepatocellular carcinoma risk

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Cite this