Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)

Joyce Y. Huang; Tricia L. Larose; Hung N. Luu; Renwei Wang; Anouar Fanidi; Karine Alcala; Victoria L. Stevens; Stephanie J. Weinstein; Demetrius Albanes; Neil E. Caporaso; Mark P. Purdue; Regina G. Ziegler; Neal D. Freedman; Qing Lan; Ross L. Prentice; Mary Pettinger; Cynthia A. Thomson; Qiuyin Cai; Jie Wu; William J. Blot; Xiao Ou Shu; Wei Zheng; Alan A. Arslan; Anne Zeleniuch-Jacquotte; Loïc Le Marchand; Lynn R. Wilkens; Christopher A. Haiman; Xuehong Zhang; Meir J. Stampfer; Jiali Han; Graham G. Giles; Allison M. Hodge; Gianluca Severi; Mikael Johansson; Kjell Grankvist; Arnulf Langhammer; Kristian Hveem; Yong Bing Xiang; Hong Lan Li; Yu Tang Gao; Kala Visvanathan; Per M. Ueland; Øivind Midttun; Arve Ulvi; Julie E. Buring; I. Min Lee; Howard D. Sesso; J. Michael Gaziano; Jonas Manjer; Caroline Relton; Woon Puay Koh; Paul Brennan; Mattias Johansson; Jian Min Yuan

doi:10.1002/ijc.32555

Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)

Joyce Y. Huang, Tricia L. Larose, Hung N. Luu, Renwei Wang, Anouar Fanidi, Karine Alcala, Victoria L. Stevens, Stephanie J. Weinstein, Demetrius Albanes, Neil E. Caporaso, Mark P. Purdue, Regina G. Ziegler, Neal D. Freedman, Qing Lan, Ross L. Prentice, Mary Pettinger, Cynthia A. Thomson, Qiuyin Cai, Jie Wu, William J. BlotXiao Ou Shu, Wei Zheng, Alan A. Arslan, Anne Zeleniuch-Jacquotte, Loïc Le Marchand, Lynn R. Wilkens, Christopher A. Haiman, Xuehong Zhang, Meir J. Stampfer, Jiali Han, Graham G. Giles, Allison M. Hodge, Gianluca Severi, Mikael Johansson, Kjell Grankvist, Arnulf Langhammer, Kristian Hveem, Yong Bing Xiang, Hong Lan Li, Yu Tang Gao, Kala Visvanathan, Per M. Ueland, Øivind Midttun, Arve Ulvi, Julie E. Buring, I. Min Lee, Howard D. Sesso, J. Michael Gaziano, Jonas Manjer, Caroline Relton, Woon Puay Koh, Paul Brennan, Mattias Johansson, Jian Min Yuan

Bloomberg School of Public Health

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

5 Scopus citations

Abstract

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case–control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20–30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all p_trend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15–1.75), 1.42 (1.14–1.76) and 1.45 (1.13–1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan–kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

Original language	English (US)
Pages (from-to)	2394-2405
Number of pages	12
Journal	International Journal of Cancer
Volume	146
Issue number	9
DOIs	https://doi.org/10.1002/ijc.32555
State	Published - May 1 2020

Keywords

kynurenine
lung cancer
neopterin
quinolinic acid
tryptophan

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1002/ijc.32555

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Huang, J. Y., Larose, T. L., Luu, H. N., Wang, R., Fanidi, A., Alcala, K., Stevens, V. L., Weinstein, S. J., Albanes, D., Caporaso, N. E., Purdue, M. P., Ziegler, R. G., Freedman, N. D., Lan, Q., Prentice, R. L., Pettinger, M., Thomson, C. A., Cai, Q., Wu, J., ... Yuan, J. M. (2020). Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3). International Journal of Cancer, 146(9), 2394-2405. https://doi.org/10.1002/ijc.32555

Huang, JY, Larose, TL, Luu, HN, Wang, R, Fanidi, A, Alcala, K, Stevens, VL, Weinstein, SJ, Albanes, D, Caporaso, NE, Purdue, MP, Ziegler, RG, Freedman, ND, Lan, Q, Prentice, RL, Pettinger, M, Thomson, CA, Cai, Q, Wu, J, Blot, WJ, Shu, XO, Zheng, W, Arslan, AA, Zeleniuch-Jacquotte, A, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Han, J, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Hveem, K, Xiang, YB, Li, HL, Gao, YT, Visvanathan, K, Ueland, PM, Midttun, Ø, Ulvi, A, Buring, JE, Lee, IM, Sesso, HD, Gaziano, JM, Manjer, J, Relton, C, Koh, WP, Brennan, P, Johansson, M & Yuan, JM 2020, 'Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)', International Journal of Cancer, vol. 146, no. 9, pp. 2394-2405. https://doi.org/10.1002/ijc.32555

@article{9964656dc536436f86a3dae7e03bb634,

title = "Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)",

abstract = "Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case–control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20–30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15–1.75), 1.42 (1.14–1.76) and 1.45 (1.13–1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan–kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.",

keywords = "kynurenine, lung cancer, neopterin, quinolinic acid, tryptophan",

author = "Huang, {Joyce Y.} and Larose, {Tricia L.} and Luu, {Hung N.} and Renwei Wang and Anouar Fanidi and Karine Alcala and Stevens, {Victoria L.} and Weinstein, {Stephanie J.} and Demetrius Albanes and Caporaso, {Neil E.} and Purdue, {Mark P.} and Ziegler, {Regina G.} and Freedman, {Neal D.} and Qing Lan and Prentice, {Ross L.} and Mary Pettinger and Thomson, {Cynthia A.} and Qiuyin Cai and Jie Wu and Blot, {William J.} and Shu, {Xiao Ou} and Wei Zheng and Arslan, {Alan A.} and Anne Zeleniuch-Jacquotte and {Le Marchand}, Lo{\"i}c and Wilkens, {Lynn R.} and Haiman, {Christopher A.} and Xuehong Zhang and Stampfer, {Meir J.} and Jiali Han and Giles, {Graham G.} and Hodge, {Allison M.} and Gianluca Severi and Mikael Johansson and Kjell Grankvist and Arnulf Langhammer and Kristian Hveem and Xiang, {Yong Bing} and Li, {Hong Lan} and Gao, {Yu Tang} and Kala Visvanathan and Ueland, {Per M.} and {\O}ivind Midttun and Arve Ulvi and Buring, {Julie E.} and Lee, {I. Min} and Sesso, {Howard D.} and Gaziano, {J. Michael} and Jonas Manjer and Caroline Relton and Koh, {Woon Puay} and Paul Brennan and Mattias Johansson and Yuan, {Jian Min}",

note = "Funding Information: We thank all participants, investigators and staff of the 20 original cohort studies that contributed data and biospecimens to the international Lung Cancer Cohort Consortium (LC3) project. For the Nurses{\textquoteright} Health Study and the Health Professionals Follow-up Study, we acknowledge following state cancer registries for their help to ascertain cancer cases: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. For the Campaign Against Cancer and Stroke (CLUE I) and the Campaign Against Cancer and Heart Disease (CLUE II) cohorts, we thank the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene for providing Cancer Incidence Data, The Lung Cancer Cohort Consortium (LC3) was supported by National Institutes of Health/National Cancer Institute grant No. 1U01CA155340. The work of T. L. Larose presented in this paper was undertaken during a postdoctoral placement at the International Agency for Research on Cancer, within the framework of an agreement between the Research Council of Norway and the Norwegian University of Science and Technology. We acknowledge the main funding sources to individual participating cohorts (Funding agency, grant number): The Nurses{\textquoteright} Health Study and the Health Professionals Follow-up Study (NIH UM1CA167552, UM1CA186107 and P01CA87969); the Shanghai Cohort Study and the Singapore Chinese Health Study (NIH R01CA1144034 and UM1CA182876); the Shanghai Men{\textquoteright}s Health Study (NIH UM1 CA173640); The Shanghai Women{\textquoteright}s Health Study (NIH UM1 CA182910); The Southern Community Cohort Study (NIH R01 CA092447 and U01 CA202979); The Women{\textquoteright}s Health Initiative (NIH contracts HHSN268201100046C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C and HHSN271201600004C); the Women{\textquoteright}s Health Study (NIH CA047988, CA182913, HL043851, HL080467 and HL099355), the Physicians{\textquoteright} Health Study (NIH CA097193, CA34944, CA40360, HL26490 and HL34595), and the New York University Women{\textquoteright}s Health Study (NIH UM1 CA182934, P30 CA016087 and P30 ES000260). The Alpha-Tocopherol Beta-Carotene Study (HHSN261201500005C and NCI Intramural Research Program); the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI) and contracts from the Division of Cancer Prevention, NCI); the Melbourne Collaborative Cohort Study (VicHealth and Cancer Council Victoria and Australian National Health and Medical Research Council grants 209057, 396414 and 1074383); The CLUE I and II (the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries); and the HUNT Study is a collaboration between NTNU (Norwegian University of Science and Technology, Faculty of Medicine and Health Sciences), Tr{\o}ndelag County Council, Central Norway Health Authority and the Norwegian Institute of Public Health. Funding Information: We thank all participants, investigators and staff of the 20 original cohort studies that contributed data and biospecimens to the international Lung Cancer Cohort Consortium (LC3) project. For the Nurses? Health Study and the Health Professionals Follow-up Study, we acknowledge following state cancer registries for their help to ascertain cancer cases: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. For the Campaign Against Cancer and Stroke (CLUE I) and the Campaign Against Cancer and Heart Disease (CLUE II) cohorts, we thank the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene for providing Cancer Incidence Data, The Lung Cancer Cohort Consortium (LC3) was supported by National Institutes of Health/National Cancer Institute grant No. 1U01CA155340. The work of T. L. Larose presented in this paper was undertaken during a postdoctoral placement at the International Agency for Research on Cancer, within the framework of an agreement between the Research Council of Norway and the Norwegian University of Science and Technology. We acknowledge the main funding sources to individual participating cohorts (Funding agency, grant number): The Nurses? Health Study and the Health Professionals Follow-up Study (NIH UM1CA167552, UM1CA186107 and P01CA87969); the Shanghai Cohort Study and the Singapore Chinese Health Study (NIH R01CA1144034 and UM1CA182876); the Shanghai Men's Health Study (NIH UM1 CA173640); The Shanghai Women's Health Study (NIH UM1 CA182910); The Southern Community Cohort Study (NIH R01 CA092447 and U01 CA202979); The Women's Health Initiative (NIH contracts HHSN268201100046C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C and HHSN271201600004C); the Women's Health Study (NIH CA047988, CA182913, HL043851, HL080467 and HL099355), the Physicians? Health Study (NIH CA097193, CA34944, CA40360, HL26490 and HL34595), and the New York University Women's Health Study (NIH UM1 CA182934, P30 CA016087 and P30 ES000260). The Alpha-Tocopherol Beta-Carotene Study (HHSN261201500005C and NCI Intramural Research Program); the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI) and contracts from the Division of Cancer Prevention, NCI); the Melbourne Collaborative Cohort Study (VicHealth and Cancer Council Victoria and Australian National Health and Medical Research Council grants 209057, 396414 and 1074383). Publisher Copyright: {\textcopyright} 2019 UICC",

year = "2020",

month = may,

day = "1",

doi = "10.1002/ijc.32555",

language = "English (US)",

volume = "146",

pages = "2394--2405",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "Wiley-Liss Inc.",

number = "9",

}

TY - JOUR

T1 - Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)

AU - Huang, Joyce Y.

AU - Larose, Tricia L.

AU - Luu, Hung N.

AU - Wang, Renwei

AU - Fanidi, Anouar

AU - Alcala, Karine

AU - Stevens, Victoria L.

AU - Weinstein, Stephanie J.

AU - Albanes, Demetrius

AU - Caporaso, Neil E.

AU - Purdue, Mark P.

AU - Ziegler, Regina G.

AU - Freedman, Neal D.

AU - Lan, Qing

AU - Prentice, Ross L.

AU - Pettinger, Mary

AU - Thomson, Cynthia A.

AU - Cai, Qiuyin

AU - Wu, Jie

AU - Blot, William J.

AU - Shu, Xiao Ou

AU - Zheng, Wei

AU - Arslan, Alan A.

AU - Zeleniuch-Jacquotte, Anne

AU - Le Marchand, Loïc

AU - Wilkens, Lynn R.

AU - Haiman, Christopher A.

AU - Zhang, Xuehong

AU - Stampfer, Meir J.

AU - Han, Jiali

AU - Giles, Graham G.

AU - Hodge, Allison M.

AU - Severi, Gianluca

AU - Johansson, Mikael

AU - Grankvist, Kjell

AU - Langhammer, Arnulf

AU - Hveem, Kristian

AU - Xiang, Yong Bing

AU - Li, Hong Lan

AU - Gao, Yu Tang

AU - Visvanathan, Kala

AU - Ueland, Per M.

AU - Midttun, Øivind

AU - Ulvi, Arve

AU - Buring, Julie E.

AU - Lee, I. Min

AU - Sesso, Howard D.

AU - Gaziano, J. Michael

AU - Manjer, Jonas

AU - Relton, Caroline

AU - Koh, Woon Puay

AU - Brennan, Paul

AU - Johansson, Mattias

AU - Yuan, Jian Min

N1 - Funding Information: We thank all participants, investigators and staff of the 20 original cohort studies that contributed data and biospecimens to the international Lung Cancer Cohort Consortium (LC3) project. For the Nurses’ Health Study and the Health Professionals Follow-up Study, we acknowledge following state cancer registries for their help to ascertain cancer cases: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. For the Campaign Against Cancer and Stroke (CLUE I) and the Campaign Against Cancer and Heart Disease (CLUE II) cohorts, we thank the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene for providing Cancer Incidence Data, The Lung Cancer Cohort Consortium (LC3) was supported by National Institutes of Health/National Cancer Institute grant No. 1U01CA155340. The work of T. L. Larose presented in this paper was undertaken during a postdoctoral placement at the International Agency for Research on Cancer, within the framework of an agreement between the Research Council of Norway and the Norwegian University of Science and Technology. We acknowledge the main funding sources to individual participating cohorts (Funding agency, grant number): The Nurses’ Health Study and the Health Professionals Follow-up Study (NIH UM1CA167552, UM1CA186107 and P01CA87969); the Shanghai Cohort Study and the Singapore Chinese Health Study (NIH R01CA1144034 and UM1CA182876); the Shanghai Men’s Health Study (NIH UM1 CA173640); The Shanghai Women’s Health Study (NIH UM1 CA182910); The Southern Community Cohort Study (NIH R01 CA092447 and U01 CA202979); The Women’s Health Initiative (NIH contracts HHSN268201100046C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C and HHSN271201600004C); the Women’s Health Study (NIH CA047988, CA182913, HL043851, HL080467 and HL099355), the Physicians’ Health Study (NIH CA097193, CA34944, CA40360, HL26490 and HL34595), and the New York University Women’s Health Study (NIH UM1 CA182934, P30 CA016087 and P30 ES000260). The Alpha-Tocopherol Beta-Carotene Study (HHSN261201500005C and NCI Intramural Research Program); the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI) and contracts from the Division of Cancer Prevention, NCI); the Melbourne Collaborative Cohort Study (VicHealth and Cancer Council Victoria and Australian National Health and Medical Research Council grants 209057, 396414 and 1074383); The CLUE I and II (the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries); and the HUNT Study is a collaboration between NTNU (Norwegian University of Science and Technology, Faculty of Medicine and Health Sciences), Trøndelag County Council, Central Norway Health Authority and the Norwegian Institute of Public Health. Funding Information: We thank all participants, investigators and staff of the 20 original cohort studies that contributed data and biospecimens to the international Lung Cancer Cohort Consortium (LC3) project. For the Nurses? Health Study and the Health Professionals Follow-up Study, we acknowledge following state cancer registries for their help to ascertain cancer cases: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. For the Campaign Against Cancer and Stroke (CLUE I) and the Campaign Against Cancer and Heart Disease (CLUE II) cohorts, we thank the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Health and Mental Hygiene for providing Cancer Incidence Data, The Lung Cancer Cohort Consortium (LC3) was supported by National Institutes of Health/National Cancer Institute grant No. 1U01CA155340. The work of T. L. Larose presented in this paper was undertaken during a postdoctoral placement at the International Agency for Research on Cancer, within the framework of an agreement between the Research Council of Norway and the Norwegian University of Science and Technology. We acknowledge the main funding sources to individual participating cohorts (Funding agency, grant number): The Nurses? Health Study and the Health Professionals Follow-up Study (NIH UM1CA167552, UM1CA186107 and P01CA87969); the Shanghai Cohort Study and the Singapore Chinese Health Study (NIH R01CA1144034 and UM1CA182876); the Shanghai Men's Health Study (NIH UM1 CA173640); The Shanghai Women's Health Study (NIH UM1 CA182910); The Southern Community Cohort Study (NIH R01 CA092447 and U01 CA202979); The Women's Health Initiative (NIH contracts HHSN268201100046C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C and HHSN271201600004C); the Women's Health Study (NIH CA047988, CA182913, HL043851, HL080467 and HL099355), the Physicians? Health Study (NIH CA097193, CA34944, CA40360, HL26490 and HL34595), and the New York University Women's Health Study (NIH UM1 CA182934, P30 CA016087 and P30 ES000260). The Alpha-Tocopherol Beta-Carotene Study (HHSN261201500005C and NCI Intramural Research Program); the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI) and contracts from the Division of Cancer Prevention, NCI); the Melbourne Collaborative Cohort Study (VicHealth and Cancer Council Victoria and Australian National Health and Medical Research Council grants 209057, 396414 and 1074383). Publisher Copyright: © 2019 UICC

PY - 2020/5/1

Y1 - 2020/5/1

N2 - Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case–control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20–30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15–1.75), 1.42 (1.14–1.76) and 1.45 (1.13–1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan–kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

AB - Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case–control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20–30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15–1.75), 1.42 (1.14–1.76) and 1.45 (1.13–1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan–kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

KW - kynurenine

KW - lung cancer

KW - neopterin

KW - quinolinic acid

KW - tryptophan

UR - http://www.scopus.com/inward/record.url?scp=85069910415&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069910415&partnerID=8YFLogxK

U2 - 10.1002/ijc.32555

DO - 10.1002/ijc.32555

M3 - Article

C2 - 31276202

AN - SCOPUS:85069910415

SN - 0020-7136

VL - 146

SP - 2394

EP - 2405

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 9

ER -

Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)

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Keywords

ASJC Scopus subject areas

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