Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Aug;18(8):1003-1016.
doi: 10.1016/j.jtho.2023.05.001. Epub 2023 May 5.

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

Chao Cheng  1 , Wei Hong  2 , Yafang Li  1 , Xiangjun Xiao  2 , James McKay  3 , Younghun Han  4 , Jinyoung Byun  4 , Bo Peng  4 , Demetrios Albanes  5 , Stephen Lam  6 , Adonina Tardon  7 , Chu Chen  8 , Stig E Bojesen  9 , Maria T Landi  5 , Mattias Johansson  3 , Angela Risch  10 , Heike Bickeböller  11 , H-Erich Wichmann  12 , David C Christiani  13 , Gad Rennert  14 , Susanne Arnold  15 , Gary Goodman  16 , John K Field  17 , Michael P A Davies  17 , Sanjay S Shete  18 , Loic Le Marchand  19 , Geoffrey Liu  20 , Rayjean J Hung  21 , Angeline S Andrew  22 , Lambertus A Kiemeney  23 , Meng Zhu  24 , Hongbing Shen  24 , Shan Zienolddiny  25 , Kjell Grankvist  26 , Mikael Johansson  27 , Angela Cox  28 , Yun-Chul Hong  29 , Jian-Min Yuan  30 , Philip Lazarus  31 , Matthew B Schabath  32 , Melinda C Aldrich  33 , Paul Brennan  3 , Yong Li  1 , Olga Gorlova  1 , Ivan Gorlov  1 , Christopher I Amos  34 ; INTEGRAL-ILCCO Lung Cancer Consortium
Affiliations

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

Chao Cheng et al. J Thorac Oncol. 2023 Aug.

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest

Dr. Aldrich discloses having consultant roles with Guardant Health; having leadership roles in American College of Epidemiology, American Society of Human Genetics, and International Lung Cancer Consortium. Dr. Schabath discloses having consultant roles with Bristol Myers Squibb. The remaining authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.. The distribution of mCA events across the human genome.
(A) Distribution of mCA events on each autosome and chromosome X. Each mCA event is shown as a line with indicated start and end positions on the corresponding chromosome. (B) Distribution of the number of autosomal and ChrX mCA events detected in each subject. As shown, most subjects have only one mCA event. (C) For each chromosome, the number of subjects with mCA gain (X-axis) and loss (Y-axis) events are counted and shown as a scatterplot. Each dot represents a chromosome. (D) The number of chromosome arm-level mCA events for each chromosome. Mosaic loss and CN-LOH events are further mapped into the long (q-arm) and short arms (p-arm). Most mosaic gain events involve the whole chromosome. (E) The co-occurrence graph for arm-level mCAs. Each edge connects two arm-level mCAs that are significantly co-occurred across subjects (FDR<0.05). Of note, p+/− and q+/− indicate the presence of mCA gain/loss event on the short and long arm, rather than gain/loss of the whole arm.
Figure 2.
Figure 2.. Association of mCAs with age and sex.
(A) Fraction of subjects with autosomal mCAs, ChrX mCAs or mChrY loss in each age group. The frequency of all types of mCAs increases with age in both males and females. (B) Comparisons of mCA rate between young (age<65) and old (age≥65) subjects. (C) Comparisons of autosomal mCA rate between males and females. Males tend to have a higher rate of autosomal gains and losses than females.
Figure 3.
Figure 3.. The presence of mCAs is associated with increased risk of lung cancer.
(A) Distribution of overall autosomal mCAs and CN-LOHs across age in lung cancer cases and controls. (B) Lung cancer cases show a significantly higher rate of autosomal mCAs, especially CN-LOHs and losses. (C-D) Distribution of overall autosomal mCAs and CN-LOHs across age in two major lung cancer subtypes, lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). (E) Arm-level autosomal mCAs enriched in lung cancer cases. Significantly enriched mCAs were marked in red. (F) The top 10 most enriched cancer genes in each type of mCAs. Significantly enriched genes were highlighted in a deeper color.
Figure 4.
Figure 4.. Association of mCAs with smoking status and racial disparity in mCAs.
(A) Distribution of mChrX and mChrY losses across age in smokers and non-smokers. (B) Smokers show a significantly higher rate of overall ChrX mCAs (mainly losses) in females and mChrY losses in males. (C-D) Racial difference in the rate of autosomal mCAs and mChrY losses. Compared with Whites, Asians tend to have less autosomal mCAs and mChrY, and Blacks tend to have less mChrY losses.
Figure 5.
Figure 5.. Genetic variants associated with mCA phenotypes.
(A-C) Genetic variants associated with autosomal mCAs, ChrX mCAs, and mChrY losses. The dashed line indicates p-value cutoff 5e-8. Genetic variants with p<1e-6 were marked in red. (D-E) The nearest protein coding genes for loci Chr1q23.3 and Chr14q32.13, respectively. Variants with the lowest p-values in each locus were labeled. Heatmaps indicate the pairwise LD r2 score between variants.
See this image and copyright information in PMC

References

    1. Jaiswal S & Ebert BL Clonal hematopoiesis in human aging and disease. Science 366, eaan4673 (2019). - PMC - PubMed
    1. Liu X, Kamatani Y & Terao C Genetics of autosomal mosaic chromosomal alteration (mCA). J. Hum. Genet 66, 879–885 (2021). - PubMed
    1. Guo X et al. Mosaic loss of human Y chromosome: what, how and why. Hum. Genet 139, 421–446 (2020). - PubMed
    1. Loh P-R, Genovese G & McCarroll SA Monogenic and polygenic inheritance become instruments for clonal selection. Nature 584, 136–141 (2020). - PMC - PubMed
    1. Terao C et al. Chromosomal alterations among age-related haematopoietic clones in Japan. Nature 584, 130–135 (2020). - PMC - PubMed

Publication types