Mosaic Chromosomal Alterations Are Associated With Increased Lung Cancer Risk: Insight From the INTEGRAL-ILCCO Cohort Analysis

Chao Cheng; Wei Hong; Yafang Li; Xiangjun Xiao; James McKay; Younghun Han; Jinyoung Byun; Bo Peng; Demetrios Albanes; Stephen Lam; Adonina Tardon; Chu Chen; Stig E. Bojesen; Maria T. Landi; Mattias Johansson; Angela Risch; Heike Bickeböller; H.-Erich Wichmann; David C. Christiani; Gad Rennert; Susanne Arnold; Gary Goodman; John K. Field; Michael P. A. Davies; Sanjay S. Shete; Loic Le Marchand; Geoffrey Liu; Rayjean J. Hung; Angeline S. Andrew; Lambertus A. Kiemeney; Meng Zhu; Hongbing Shen; Shan Zienolddiny; Kjell Grankvist; Mikael Johansson; Angela Cox; Yun-Chul Hong; Jian-Min Yuan; Philip Lazarus; Matthew B. Schabath; Melinda C. Aldrich; Paul Brennan; Yong Li; Olga Gorlova; Ivan Gorlov; Christopher I. Amos; International Lung Cancer Consortium (INTEGRAL-ILCCO)

doi:10.1016/j.jtho.2023.05.001

Mosaic Chromosomal Alterations Are Associated With Increased Lung Cancer Risk: Insight From the INTEGRAL-ILCCO Cohort Analysis

Chao Cheng, Wei Hong, Yafang Li, Xiangjun Xiao, James McKay, Younghun Han, Jinyoung Byun, Bo Peng, Demetrios Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Maria T. Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H.-Erich Wichmann, David C. Christiani, Gad RennertSusanne Arnold, Gary Goodman, John K. Field, Michael P. A. Davies, Sanjay S. Shete, Loic Le Marchand, Geoffrey Liu, Rayjean J. Hung, Angeline S. Andrew, Lambertus A. Kiemeney, Meng Zhu, Hongbing Shen, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Angela Cox, Yun-Chul Hong, Jian-Min Yuan, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Paul Brennan, Yong Li, Olga Gorlova, Ivan Gorlov, Christopher I. Amos^*, International Lung Cancer Consortium (INTEGRAL-ILCCO)

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstract

Introduction: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer. Methods: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls. Results: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal mCAs were detected in 4.3% of subjects, in addition to ChrX mCAs in 3.6% of females and mChrY losses in 9.6% of males. Multivariable logistic regression analysis indicated that the presence of autosomal mCAs in white blood cells was associated with an increased lung cancer risk after adjusting for key confounding factors, including age, sex, smoking status, and race. This association was mainly driven by a specific type of mCAs: copy-neutral loss of heterozygosity on autosomal chromosomes. The association between autosome copy-neutral loss of heterozygosity and increased risk of lung cancer was further confirmed in two major histologic subtypes, lung adenocarcinoma and squamous cell carcinoma. In addition, we observed a significant increase of ChrX mCAs and mChrY losses in smokers compared with nonsmokers and racial differences in certain types of mCA events. Conclusions: Our study established a link between mCAs in white blood cells and increased risk of lung cancer.

Originalsprog	Engelsk
Tidsskrift	Journal of Thoracic Oncology
Vol/bind	18
Udgave nummer	8
Sider (fra-til)	1003-1016
Antal sider	14
ISSN	1556-0864
DOI	https://doi.org/10.1016/j.jtho.2023.05.001
Status	Udgivet - 2023

Bibliografisk note

Funding Information:
This study is supported by the Cancer Prevention Research Institute of Texas (RR180061 to Dr. Cheng and RR170048 to Dr. Amos), the National Cancer Institute of the National Institutes of Health (1R01CA269764 to Dr. Cheng), and the National Natural Science Foundation of China (81820108028 to Dr. Shen). Dr. Cheng and Dr. Amos are Cancer Prevention Research Institute of Texas Scholars in Cancer Research. Vanderbilt University Medical Center’s BioVU is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from the National Center for Advancing Translational Sciences of the National Institutes of Health. Where authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/WHO.

Funding Information:
This study is supported by the Cancer Prevention Research Institute of Texas (RR180061 to Dr. Cheng and RR170048 to Dr. Amos), the National Cancer Institute of the National Institutes of Health (1R01CA269764 to Dr. Cheng), and the National Natural Science Foundation of China (81820108028 to Dr. Shen). Dr. Cheng and Dr. Amos are Cancer Prevention Research Institute of Texas Scholars in Cancer Research. Vanderbilt University Medical Center's BioVU is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from the National Center for Advancing Translational Sciences of the National Institutes of Health. Where authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/WHO.

Publisher Copyright:
© 2023

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10.1016/j.jtho.2023.05.001

Post-printAccepteret manuskript, 1,49 MBLicens: CC BY-NC-ND

Citationsformater

Cheng, C., Hong, W., Li, Y., Xiao, X., McKay, J., Han, Y., Byun, J., Peng, B., Albanes, D., Lam, S., Tardon, A., Chen, C., Bojesen, S. E., Landi, M. T., Johansson, M., Risch, A., Bickeböller, H., Wichmann, H. -E., Christiani, D. C., ... International Lung Cancer Consortium (INTEGRAL-ILCCO) (2023). Mosaic Chromosomal Alterations Are Associated With Increased Lung Cancer Risk: Insight From the INTEGRAL-ILCCO Cohort Analysis. Journal of Thoracic Oncology, 18(8), 1003-1016. https://doi.org/10.1016/j.jtho.2023.05.001

Mosaic Chromosomal Alterations Are Associated With Increased Lung Cancer Risk : Insight From the INTEGRAL-ILCCO Cohort Analysis. / Cheng, Chao; Hong, Wei; Li, Yafang; Xiao, Xiangjun; McKay, James; Han, Younghun; Byun, Jinyoung; Peng, Bo; Albanes, Demetrios; Lam, Stephen; Tardon, Adonina; Chen, Chu; Bojesen, Stig E.; Landi, Maria T.; Johansson, Mattias; Risch, Angela; Bickeböller, Heike; Wichmann, H.-Erich; Christiani, David C.; Rennert, Gad; Arnold, Susanne; Goodman, Gary; Field, John K.; Davies, Michael P. A.; Shete, Sanjay S.; Le Marchand, Loic; Liu, Geoffrey; Hung, Rayjean J.; Andrew, Angeline S.; Kiemeney, Lambertus A.; Zhu, Meng; Shen, Hongbing; Zienolddiny, Shan; Grankvist, Kjell; Johansson, Mikael; Cox, Angela; Hong, Yun-Chul; Yuan, Jian-Min; Lazarus, Philip; Schabath, Matthew B.; Aldrich, Melinda C.; Brennan, Paul; Li, Yong; Gorlova, Olga; Gorlov, Ivan; Amos, Christopher I.; International Lung Cancer Consortium (INTEGRAL-ILCCO).

I: Journal of Thoracic Oncology, Bind 18, Nr. 8, 2023, s. 1003-1016.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Cheng, C, Hong, W, Li, Y, Xiao, X, McKay, J, Han, Y, Byun, J, Peng, B, Albanes, D, Lam, S, Tardon, A, Chen, C, Bojesen, SE, Landi, MT, Johansson, M, Risch, A, Bickeböller, H, Wichmann, H-E, Christiani, DC, Rennert, G, Arnold, S, Goodman, G, Field, JK, Davies, MPA, Shete, SS, Le Marchand, L, Liu, G, Hung, RJ, Andrew, AS, Kiemeney, LA, Zhu, M, Shen, H, Zienolddiny, S, Grankvist, K, Johansson, M, Cox, A, Hong, Y-C, Yuan, J-M, Lazarus, P, Schabath, MB, Aldrich, MC, Brennan, P, Li, Y, Gorlova, O, Gorlov, I, Amos, CI & International Lung Cancer Consortium (INTEGRAL-ILCCO) 2023, 'Mosaic Chromosomal Alterations Are Associated With Increased Lung Cancer Risk: Insight From the INTEGRAL-ILCCO Cohort Analysis', Journal of Thoracic Oncology, bind 18, nr. 8, s. 1003-1016. https://doi.org/10.1016/j.jtho.2023.05.001

Cheng, Chao ; Hong, Wei ; Li, Yafang ; Xiao, Xiangjun ; McKay, James ; Han, Younghun ; Byun, Jinyoung ; Peng, Bo ; Albanes, Demetrios ; Lam, Stephen ; Tardon, Adonina ; Chen, Chu ; Bojesen, Stig E. ; Landi, Maria T. ; Johansson, Mattias ; Risch, Angela ; Bickeböller, Heike ; Wichmann, H.-Erich ; Christiani, David C. ; Rennert, Gad ; Arnold, Susanne ; Goodman, Gary ; Field, John K. ; Davies, Michael P. A. ; Shete, Sanjay S. ; Le Marchand, Loic ; Liu, Geoffrey ; Hung, Rayjean J. ; Andrew, Angeline S. ; Kiemeney, Lambertus A. ; Zhu, Meng ; Shen, Hongbing ; Zienolddiny, Shan ; Grankvist, Kjell ; Johansson, Mikael ; Cox, Angela ; Hong, Yun-Chul ; Yuan, Jian-Min ; Lazarus, Philip ; Schabath, Matthew B. ; Aldrich, Melinda C. ; Brennan, Paul ; Li, Yong ; Gorlova, Olga ; Gorlov, Ivan ; Amos, Christopher I. ; International Lung Cancer Consortium (INTEGRAL-ILCCO). / Mosaic Chromosomal Alterations Are Associated With Increased Lung Cancer Risk : Insight From the INTEGRAL-ILCCO Cohort Analysis. I: Journal of Thoracic Oncology. 2023 ; Bind 18, Nr. 8. s. 1003-1016.

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title = "Mosaic Chromosomal Alterations Are Associated With Increased Lung Cancer Risk: Insight From the INTEGRAL-ILCCO Cohort Analysis",

abstract = "Introduction: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer. Methods: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls. Results: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal mCAs were detected in 4.3% of subjects, in addition to ChrX mCAs in 3.6% of females and mChrY losses in 9.6% of males. Multivariable logistic regression analysis indicated that the presence of autosomal mCAs in white blood cells was associated with an increased lung cancer risk after adjusting for key confounding factors, including age, sex, smoking status, and race. This association was mainly driven by a specific type of mCAs: copy-neutral loss of heterozygosity on autosomal chromosomes. The association between autosome copy-neutral loss of heterozygosity and increased risk of lung cancer was further confirmed in two major histologic subtypes, lung adenocarcinoma and squamous cell carcinoma. In addition, we observed a significant increase of ChrX mCAs and mChrY losses in smokers compared with nonsmokers and racial differences in certain types of mCA events. Conclusions: Our study established a link between mCAs in white blood cells and increased risk of lung cancer.",

keywords = "Clonal hematopoiesis, Loss of heterozygosity, Lung cancer risk, Mosaic chromosomal alterations",

author = "Chao Cheng and Wei Hong and Yafang Li and Xiangjun Xiao and James McKay and Younghun Han and Jinyoung Byun and Bo Peng and Demetrios Albanes and Stephen Lam and Adonina Tardon and Chu Chen and Bojesen, {Stig E.} and Landi, {Maria T.} and Mattias Johansson and Angela Risch and Heike Bickeb{\"o}ller and H.-Erich Wichmann and Christiani, {David C.} and Gad Rennert and Susanne Arnold and Gary Goodman and Field, {John K.} and Davies, {Michael P. A.} and Shete, {Sanjay S.} and {Le Marchand}, Loic and Geoffrey Liu and Hung, {Rayjean J.} and Andrew, {Angeline S.} and Kiemeney, {Lambertus A.} and Meng Zhu and Hongbing Shen and Shan Zienolddiny and Kjell Grankvist and Mikael Johansson and Angela Cox and Yun-Chul Hong and Jian-Min Yuan and Philip Lazarus and Schabath, {Matthew B.} and Aldrich, {Melinda C.} and Paul Brennan and Yong Li and Olga Gorlova and Ivan Gorlov and Amos, {Christopher I.} and {International Lung Cancer Consortium (INTEGRAL-ILCCO)}",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

doi = "10.1016/j.jtho.2023.05.001",

language = "English",

volume = "18",

pages = "1003--1016",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

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TY - JOUR

T1 - Mosaic Chromosomal Alterations Are Associated With Increased Lung Cancer Risk

T2 - Insight From the INTEGRAL-ILCCO Cohort Analysis

AU - Cheng, Chao

AU - Hong, Wei

AU - Li, Yafang

AU - Xiao, Xiangjun

AU - McKay, James

AU - Han, Younghun

AU - Byun, Jinyoung

AU - Peng, Bo

AU - Albanes, Demetrios

AU - Lam, Stephen

AU - Tardon, Adonina

AU - Chen, Chu

AU - Bojesen, Stig E.

AU - Landi, Maria T.

AU - Johansson, Mattias

AU - Risch, Angela

AU - Bickeböller, Heike

AU - Wichmann, H.-Erich

AU - Christiani, David C.

AU - Rennert, Gad

AU - Arnold, Susanne

AU - Goodman, Gary

AU - Field, John K.

AU - Davies, Michael P. A.

AU - Shete, Sanjay S.

AU - Le Marchand, Loic

AU - Liu, Geoffrey

AU - Hung, Rayjean J.

AU - Andrew, Angeline S.

AU - Kiemeney, Lambertus A.

AU - Zhu, Meng

AU - Shen, Hongbing

AU - Zienolddiny, Shan

AU - Grankvist, Kjell

AU - Johansson, Mikael

AU - Cox, Angela

AU - Hong, Yun-Chul

AU - Yuan, Jian-Min

AU - Lazarus, Philip

AU - Schabath, Matthew B.

AU - Aldrich, Melinda C.

AU - Brennan, Paul

AU - Li, Yong

AU - Gorlova, Olga

AU - Gorlov, Ivan

AU - Amos, Christopher I.

AU - International Lung Cancer Consortium (INTEGRAL-ILCCO)

PY - 2023

Y1 - 2023

N2 - Introduction: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer. Methods: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls. Results: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal mCAs were detected in 4.3% of subjects, in addition to ChrX mCAs in 3.6% of females and mChrY losses in 9.6% of males. Multivariable logistic regression analysis indicated that the presence of autosomal mCAs in white blood cells was associated with an increased lung cancer risk after adjusting for key confounding factors, including age, sex, smoking status, and race. This association was mainly driven by a specific type of mCAs: copy-neutral loss of heterozygosity on autosomal chromosomes. The association between autosome copy-neutral loss of heterozygosity and increased risk of lung cancer was further confirmed in two major histologic subtypes, lung adenocarcinoma and squamous cell carcinoma. In addition, we observed a significant increase of ChrX mCAs and mChrY losses in smokers compared with nonsmokers and racial differences in certain types of mCA events. Conclusions: Our study established a link between mCAs in white blood cells and increased risk of lung cancer.

AB - Introduction: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer. Methods: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls. Results: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal mCAs were detected in 4.3% of subjects, in addition to ChrX mCAs in 3.6% of females and mChrY losses in 9.6% of males. Multivariable logistic regression analysis indicated that the presence of autosomal mCAs in white blood cells was associated with an increased lung cancer risk after adjusting for key confounding factors, including age, sex, smoking status, and race. This association was mainly driven by a specific type of mCAs: copy-neutral loss of heterozygosity on autosomal chromosomes. The association between autosome copy-neutral loss of heterozygosity and increased risk of lung cancer was further confirmed in two major histologic subtypes, lung adenocarcinoma and squamous cell carcinoma. In addition, we observed a significant increase of ChrX mCAs and mChrY losses in smokers compared with nonsmokers and racial differences in certain types of mCA events. Conclusions: Our study established a link between mCAs in white blood cells and increased risk of lung cancer.

KW - Clonal hematopoiesis

KW - Loss of heterozygosity

KW - Lung cancer risk

KW - Mosaic chromosomal alterations

U2 - 10.1016/j.jtho.2023.05.001

DO - 10.1016/j.jtho.2023.05.001

M3 - Journal article

C2 - 37150255

AN - SCOPUS:85163295925

VL - 18

SP - 1003

EP - 1016

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

SN - 1556-0864

IS - 8

ER -