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

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

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

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.

Original language	English
Pages (from-to)	1003-1016
Number of pages	14
Journal	Journal of Thoracic Oncology
Volume	18
Issue number	8
DOIs	https://doi.org/10.1016/j.jtho.2023.05.001
State	Published - Aug 2023

Bibliographical note

Publisher Copyright:
© 2023

Funding

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. 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.

Funders	Funder number
Vanderbilt CTSA	UL1 TR000445
National Institutes of Health (NIH)	1R01CA269764
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute
World Health Organization
Cancer Prevention and Research Institute of Texas	RR170048, RR180061
Cancer Prevention and Research Institute of Texas
National Center for Advancing Translational Sciences (NCATS)
Centre International de Recherche sur le Cancer
National Natural Science Foundation of China (NSFC)	81820108028
National Natural Science Foundation of China (NSFC)

Keywords

Clonal hematopoiesis
Loss of heterozygosity
Lung cancer risk
Mosaic chromosomal alterations

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jtho.2023.05.001

Cite this

@article{d20a18d744144e20a3e1e3bab8d95448,

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 Wichmann, {H. Erich} 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 Hong, {Yun Chul} and Yuan, {Jian Min} 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.}",

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

year = "2023",

month = aug,

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

language = "English",

volume = "18",

pages = "1003--1016",

number = "8",

}

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.

PY - 2023/8

Y1 - 2023/8

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

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UR - http://www.scopus.com/inward/citedby.url?scp=85163295925&partnerID=8YFLogxK

U2 - 10.1016/j.jtho.2023.05.001

DO - 10.1016/j.jtho.2023.05.001

M3 - Article

C2 - 37150255

AN - SCOPUS:85163295925

SN - 1556-0864

VL - 18

SP - 1003

EP - 1016

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

IS - 8

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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