Prospective association of liver function biomarkers with development of hepatobiliary cancers

Magdalena Stepien; Veronika Fedirko; Talita Duarte-Salles; Pietro Ferrari; Heinz Freisling; Elisabeth Trepo; Antonia Trichopoulou; Christina Bamia; Elisabete Weiderpass; Anja Olsen; Anne Tjønneland; Kim Overvad; Marie Christine Boutron-Ruault; Guy Fagherazzi; Antoine Racine; Tilman Kühn; Rudolf Kaaks; Krasimira Aleksandrova; Heiner Boeing; Pagona Lagiou; Vassiliki Benetou; Dimitrios Trichopoulos; Domenico Palli; Sara Grioni; Rosario Tumino; Alessio Naccarati; Salvatore Panico; H. Bas Bueno-de-Mesquita; Petra H. Peeters; Eiliv Lund; J. Ramón Quirós; Osmel Companioni Nápoles; María José Sánchez; Miren Dorronsoro; José María Huerta; Eva Ardanaz; Bodil Ohlsson; Klas Sjöberg; Mårten Werner; Hanna Nystrom; Kay Tee Khaw; Timothy J. Key; Marc Gunter; Amanda Cross; Elio Riboli; Isabelle Romieu; Mazda Jenab

doi:10.1016/j.canep.2016.01.002

Prospective association of liver function biomarkers with development of hepatobiliary cancers

Magdalena Stepien, Veronika Fedirko, Talita Duarte-Salles, Pietro Ferrari, Heinz Freisling, Elisabeth Trepo, Antonia Trichopoulou, Christina Bamia, Elisabete Weiderpass, Anja Olsen, Anne Tjønneland, Kim Overvad, Marie Christine Boutron-Ruault, Guy Fagherazzi, Antoine Racine, Tilman Kühn, Rudolf Kaaks, Krasimira Aleksandrova, Heiner Boeing, Pagona LagiouVassiliki Benetou, Dimitrios Trichopoulos, Domenico Palli, Sara Grioni, Rosario Tumino, Alessio Naccarati, Salvatore Panico, H. Bas Bueno-de-Mesquita, Petra H. Peeters, Eiliv Lund, J. Ramón Quirós, Osmel Companioni Nápoles, María José Sánchez, Miren Dorronsoro, José María Huerta, Eva Ardanaz, Bodil Ohlsson, Klas Sjöberg, Mårten Werner, Hanna Nystrom, Kay Tee Khaw, Timothy J. Key, Marc Gunter, Amanda Cross, Elio Riboli, Isabelle Romieu, Mazda Jenab^*

^*Corresponding author for this work

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

35 Citations (Scopus)

Abstract

Introduction: Serum liver biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used as indicators of liver disease, but there is currently little data on their prospective association with risk of hepatobiliary cancers. Methods: A nested-case control study was conducted within the prospective EPIC cohort (>520,000 participants, 10 European countries). After a mean 7.5 mean years of follow-up, 121 hepatocellular carcinoma (HCC), 34 intrahepatic bile duct (IHBC) and 131 gallbladder and biliary tract (GBTC) cases were identified and matched to 2 controls each. Circulating biomarkers were measured in serum taken at recruitment into the cohort, prior to cancer diagnosis. Multivariable adjusted conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI). Results: In multivariable models, 1SD increase of each log-transformed biomarker was positively associated with HCC risk (OR(GGT) = 4.23, 95%CI:2.72-6.59; OR(ALP) = 3.43, 95%CI:2.31-5.10;OR(AST) = 3.00, 95%CI:2.04-4.42; OR(ALT) = 2.69, 95%CI:1.89-3.84; OR(Bilirubin) = 2.25, 95%CI:1.58-3.20). Each liver enzyme (OR(GGT) = 4.98; 95%CI:1.75-14.17; OR(AST) = 3.10, 95%CI:1.04-9.30; OR(ALT) = 2.86, 95%CI:1.26-6.48, OR(ALP) = 2.31, 95%CI:1.10-4.86) but not bilirubin (OR(Bilirubin) = 1.46,95%CI:0.85-2.51) showed a significant association with IHBC. Only ALP was significantly associated with GBTC risk (OR(ALP) = 1.59, 95%CI:1.20-2.09). Conclusion: This study shows positive associations between circulating liver biomarkers in sera collected prior to cancer diagnoses and the risks of developing HCC or IHBC, but not GBTC.

Original language	English
Pages (from-to)	179-187
Number of pages	9
Journal	Cancer Epidemiology
Volume	40
DOIs	https://doi.org/10.1016/j.canep.2016.01.002
Publication status	Published - 1 Feb 2016
Externally published	Yes

Keywords

Biological markers
Hepatobiliary cancer
Liver function test
Nested case-control study
Prospective cohort

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10.1016/j.canep.2016.01.002

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Stepien, M., Fedirko, V., Duarte-Salles, T., Ferrari, P., Freisling, H., Trepo, E., Trichopoulou, A., Bamia, C., Weiderpass, E., Olsen, A., Tjønneland, A., Overvad, K., Boutron-Ruault, M. C., Fagherazzi, G., Racine, A., Kühn, T., Kaaks, R., Aleksandrova, K., Boeing, H., ... Jenab, M. (2016). Prospective association of liver function biomarkers with development of hepatobiliary cancers. Cancer Epidemiology, 40, 179-187. https://doi.org/10.1016/j.canep.2016.01.002

@article{9316390e99654ff7a987ee6ba4ea7d26,

title = "Prospective association of liver function biomarkers with development of hepatobiliary cancers",

abstract = "Introduction: Serum liver biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used as indicators of liver disease, but there is currently little data on their prospective association with risk of hepatobiliary cancers. Methods: A nested-case control study was conducted within the prospective EPIC cohort (>520,000 participants, 10 European countries). After a mean 7.5 mean years of follow-up, 121 hepatocellular carcinoma (HCC), 34 intrahepatic bile duct (IHBC) and 131 gallbladder and biliary tract (GBTC) cases were identified and matched to 2 controls each. Circulating biomarkers were measured in serum taken at recruitment into the cohort, prior to cancer diagnosis. Multivariable adjusted conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI). Results: In multivariable models, 1SD increase of each log-transformed biomarker was positively associated with HCC risk (OR(GGT) = 4.23, 95%CI:2.72-6.59; OR(ALP) = 3.43, 95%CI:2.31-5.10;OR(AST) = 3.00, 95%CI:2.04-4.42; OR(ALT) = 2.69, 95%CI:1.89-3.84; OR(Bilirubin) = 2.25, 95%CI:1.58-3.20). Each liver enzyme (OR(GGT) = 4.98; 95%CI:1.75-14.17; OR(AST) = 3.10, 95%CI:1.04-9.30; OR(ALT) = 2.86, 95%CI:1.26-6.48, OR(ALP) = 2.31, 95%CI:1.10-4.86) but not bilirubin (OR(Bilirubin) = 1.46,95%CI:0.85-2.51) showed a significant association with IHBC. Only ALP was significantly associated with GBTC risk (OR(ALP) = 1.59, 95%CI:1.20-2.09). Conclusion: This study shows positive associations between circulating liver biomarkers in sera collected prior to cancer diagnoses and the risks of developing HCC or IHBC, but not GBTC.",

keywords = "Biological markers, Hepatobiliary cancer, Liver function test, Nested case-control study, Prospective cohort",

author = "Magdalena Stepien and Veronika Fedirko and Talita Duarte-Salles and Pietro Ferrari and Heinz Freisling and Elisabeth Trepo and Antonia Trichopoulou and Christina Bamia and Elisabete Weiderpass and Anja Olsen and Anne Tj{\o}nneland and Kim Overvad and Boutron-Ruault, {Marie Christine} and Guy Fagherazzi and Antoine Racine and Tilman K{\"u}hn and Rudolf Kaaks and Krasimira Aleksandrova and Heiner Boeing and Pagona Lagiou and Vassiliki Benetou and Dimitrios Trichopoulos and Domenico Palli and Sara Grioni and Rosario Tumino and Alessio Naccarati and Salvatore Panico and Bueno-de-Mesquita, {H. Bas} and Peeters, {Petra H.} and Eiliv Lund and Quir{\'o}s, {J. Ram{\'o}n} and N{\'a}poles, {Osmel Companioni} and S{\'a}nchez, {Mar{\'i}a Jos{\'e}} and Miren Dorronsoro and Huerta, {Jos{\'e} Mar{\'i}a} and Eva Ardanaz and Bodil Ohlsson and Klas Sj{\"o}berg and M{\aa}rten Werner and Hanna Nystrom and Khaw, {Kay Tee} and Key, {Timothy J.} and Marc Gunter and Amanda Cross and Elio Riboli and Isabelle Romieu and Mazda Jenab",

note = "Funding Information: Financial support : This work was supported by the French National Cancer Institute (L{\textquoteright}Institut National du Cancer; INCA) (grant number 2009-139; PI: M. Jenab). The coordination of EPIC is financially supported by the European Commission (DG-SANCO); and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer; Institut Gustave Roussy; Mutuelle G{\'e}n{\'e}rale de l{\textquoteright}Education Nationale; and Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ); and Federal Ministry of Education and Research (Germany); Stavros Niarchos Foundation; Hellenic Health Foundation; and Ministry of Health and Social Solidarity (Greece); Italian Association for Research on Cancer (AIRC); National Research Council; and AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands (the Netherlands); European Research Council (ERC) (grant number ERC-2009-AdG 232997) and Nordforsk; and Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS); Regional Governments of Andaluc{\'i}a, Asturias, Basque Country, Murcia (No. 6236) and Navarra; and ISCIII RETIC (RD06/0020) and the Catalan Institute of Oncology. (Spain); Swedish Cancer Society; Swedish Scientific Council; and Regional Government of Sk{\aa}ne and V{\"a}sterbotten (Sweden); Cancer Research UK; Medical Research Council; Stroke Association; British Heart Foundation; Department of Health; Food Standards Agency; and Wellcome Trust (UK). Publisher Copyright: {\textcopyright} 2016 Elsevier Ltd.",

year = "2016",

month = feb,

day = "1",

doi = "10.1016/j.canep.2016.01.002",

language = "English",

volume = "40",

pages = "179--187",

journal = "Cancer Epidemiology",

issn = "1877-7821",

publisher = "Elsevier BV",

}

Stepien, M, Fedirko, V, Duarte-Salles, T, Ferrari, P, Freisling, H, Trepo, E, Trichopoulou, A, Bamia, C, Weiderpass, E, Olsen, A, Tjønneland, A, Overvad, K, Boutron-Ruault, MC, Fagherazzi, G, Racine, A, Kühn, T, Kaaks, R, Aleksandrova, K, Boeing, H, Lagiou, P, Benetou, V, Trichopoulos, D, Palli, D, Grioni, S, Tumino, R, Naccarati, A, Panico, S, Bueno-de-Mesquita, HB, Peeters, PH, Lund, E, Quirós, JR, Nápoles, OC, Sánchez, MJ, Dorronsoro, M, Huerta, JM, Ardanaz, E, Ohlsson, B, Sjöberg, K, Werner, M, Nystrom, H, Khaw, KT, Key, TJ, Gunter, M, Cross, A, Riboli, E, Romieu, I & Jenab, M 2016, 'Prospective association of liver function biomarkers with development of hepatobiliary cancers', Cancer Epidemiology, vol. 40, pp. 179-187. https://doi.org/10.1016/j.canep.2016.01.002

TY - JOUR

T1 - Prospective association of liver function biomarkers with development of hepatobiliary cancers

AU - Stepien, Magdalena

AU - Fedirko, Veronika

AU - Duarte-Salles, Talita

AU - Ferrari, Pietro

AU - Freisling, Heinz

AU - Trepo, Elisabeth

AU - Trichopoulou, Antonia

AU - Bamia, Christina

AU - Weiderpass, Elisabete

AU - Olsen, Anja

AU - Tjønneland, Anne

AU - Overvad, Kim

AU - Boutron-Ruault, Marie Christine

AU - Fagherazzi, Guy

AU - Racine, Antoine

AU - Kühn, Tilman

AU - Kaaks, Rudolf

AU - Aleksandrova, Krasimira

AU - Boeing, Heiner

AU - Lagiou, Pagona

AU - Benetou, Vassiliki

AU - Trichopoulos, Dimitrios

AU - Palli, Domenico

AU - Grioni, Sara

AU - Tumino, Rosario

AU - Naccarati, Alessio

AU - Panico, Salvatore

AU - Bueno-de-Mesquita, H. Bas

AU - Peeters, Petra H.

AU - Lund, Eiliv

AU - Quirós, J. Ramón

AU - Nápoles, Osmel Companioni

AU - Sánchez, María José

AU - Dorronsoro, Miren

AU - Huerta, José María

AU - Ardanaz, Eva

AU - Ohlsson, Bodil

AU - Sjöberg, Klas

AU - Werner, Mårten

AU - Nystrom, Hanna

AU - Khaw, Kay Tee

AU - Key, Timothy J.

AU - Gunter, Marc

AU - Cross, Amanda

AU - Riboli, Elio

AU - Romieu, Isabelle

AU - Jenab, Mazda

N1 - Funding Information: Financial support : This work was supported by the French National Cancer Institute (L’Institut National du Cancer; INCA) (grant number 2009-139; PI: M. Jenab). The coordination of EPIC is financially supported by the European Commission (DG-SANCO); and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer; Institut Gustave Roussy; Mutuelle Générale de l’Education Nationale; and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ); and Federal Ministry of Education and Research (Germany); Stavros Niarchos Foundation; Hellenic Health Foundation; and Ministry of Health and Social Solidarity (Greece); Italian Association for Research on Cancer (AIRC); National Research Council; and AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds; Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); and Statistics Netherlands (the Netherlands); European Research Council (ERC) (grant number ERC-2009-AdG 232997) and Nordforsk; and Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS); Regional Governments of Andalucía, Asturias, Basque Country, Murcia (No. 6236) and Navarra; and ISCIII RETIC (RD06/0020) and the Catalan Institute of Oncology. (Spain); Swedish Cancer Society; Swedish Scientific Council; and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK; Medical Research Council; Stroke Association; British Heart Foundation; Department of Health; Food Standards Agency; and Wellcome Trust (UK). Publisher Copyright: © 2016 Elsevier Ltd.

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Introduction: Serum liver biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used as indicators of liver disease, but there is currently little data on their prospective association with risk of hepatobiliary cancers. Methods: A nested-case control study was conducted within the prospective EPIC cohort (>520,000 participants, 10 European countries). After a mean 7.5 mean years of follow-up, 121 hepatocellular carcinoma (HCC), 34 intrahepatic bile duct (IHBC) and 131 gallbladder and biliary tract (GBTC) cases were identified and matched to 2 controls each. Circulating biomarkers were measured in serum taken at recruitment into the cohort, prior to cancer diagnosis. Multivariable adjusted conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI). Results: In multivariable models, 1SD increase of each log-transformed biomarker was positively associated with HCC risk (OR(GGT) = 4.23, 95%CI:2.72-6.59; OR(ALP) = 3.43, 95%CI:2.31-5.10;OR(AST) = 3.00, 95%CI:2.04-4.42; OR(ALT) = 2.69, 95%CI:1.89-3.84; OR(Bilirubin) = 2.25, 95%CI:1.58-3.20). Each liver enzyme (OR(GGT) = 4.98; 95%CI:1.75-14.17; OR(AST) = 3.10, 95%CI:1.04-9.30; OR(ALT) = 2.86, 95%CI:1.26-6.48, OR(ALP) = 2.31, 95%CI:1.10-4.86) but not bilirubin (OR(Bilirubin) = 1.46,95%CI:0.85-2.51) showed a significant association with IHBC. Only ALP was significantly associated with GBTC risk (OR(ALP) = 1.59, 95%CI:1.20-2.09). Conclusion: This study shows positive associations between circulating liver biomarkers in sera collected prior to cancer diagnoses and the risks of developing HCC or IHBC, but not GBTC.

AB - Introduction: Serum liver biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used as indicators of liver disease, but there is currently little data on their prospective association with risk of hepatobiliary cancers. Methods: A nested-case control study was conducted within the prospective EPIC cohort (>520,000 participants, 10 European countries). After a mean 7.5 mean years of follow-up, 121 hepatocellular carcinoma (HCC), 34 intrahepatic bile duct (IHBC) and 131 gallbladder and biliary tract (GBTC) cases were identified and matched to 2 controls each. Circulating biomarkers were measured in serum taken at recruitment into the cohort, prior to cancer diagnosis. Multivariable adjusted conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI). Results: In multivariable models, 1SD increase of each log-transformed biomarker was positively associated with HCC risk (OR(GGT) = 4.23, 95%CI:2.72-6.59; OR(ALP) = 3.43, 95%CI:2.31-5.10;OR(AST) = 3.00, 95%CI:2.04-4.42; OR(ALT) = 2.69, 95%CI:1.89-3.84; OR(Bilirubin) = 2.25, 95%CI:1.58-3.20). Each liver enzyme (OR(GGT) = 4.98; 95%CI:1.75-14.17; OR(AST) = 3.10, 95%CI:1.04-9.30; OR(ALT) = 2.86, 95%CI:1.26-6.48, OR(ALP) = 2.31, 95%CI:1.10-4.86) but not bilirubin (OR(Bilirubin) = 1.46,95%CI:0.85-2.51) showed a significant association with IHBC. Only ALP was significantly associated with GBTC risk (OR(ALP) = 1.59, 95%CI:1.20-2.09). Conclusion: This study shows positive associations between circulating liver biomarkers in sera collected prior to cancer diagnoses and the risks of developing HCC or IHBC, but not GBTC.

KW - Biological markers

KW - Hepatobiliary cancer

KW - Liver function test

KW - Nested case-control study

KW - Prospective cohort

UR - http://www.scopus.com/inward/record.url?scp=84960091550&partnerID=8YFLogxK

U2 - 10.1016/j.canep.2016.01.002

DO - 10.1016/j.canep.2016.01.002

M3 - Article

C2 - 26773278

AN - SCOPUS:84960091550

SN - 1877-7821

VL - 40

SP - 179

EP - 187

JO - Cancer Epidemiology

JF - Cancer Epidemiology

ER -

Prospective association of liver function biomarkers with development of hepatobiliary cancers

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