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

Chao Cheng1, Wei Hong2, Yafang Li1

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Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
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Summary

Mosaic chromosomal alterations (mCAs) in white blood cells are linked to a higher risk of lung cancer. This study analyzed genetic data from over 33,000 individuals to establish this association.

Keywords:
Clonal hematopoiesisLoss of heterozygosityLung cancer riskMosaic chromosomal alterations

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Area of Science:

  • Genetics
  • Oncology
  • Hematology

Background:

  • Mosaic chromosomal alterations (mCAs) in white blood cells are an understudied form of clonal hematopoiesis (CH).
  • Emerging evidence suggests a potential association between mCAs and nonhematological cancers, particularly lung cancer.

Purpose of the Study:

  • To investigate the association between mosaic chromosomal alterations (mCAs) in white blood cells and lung cancer risk.
  • To identify specific types of mCAs and their correlation with lung cancer development.

Main Methods:

  • Utilized high-density genotyping data from the OncoArray study (INTEGRAL-ILCCO) comprising 18,221 lung cancer cases and 14,825 controls.
  • Identified autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses.
  • Performed multivariable logistic regression analysis adjusting for age, sex, smoking status, and race.

Main Results:

  • Autosomal mCAs were found in 4.3% of subjects, ChrX mCAs in 3.6% of females, and mChrY losses in 9.6% of males.
  • The presence of autosomal mCAs was associated with an increased lung cancer risk, primarily driven by copy-neutral loss of heterozygosity.
  • This association was confirmed in lung adenocarcinoma and squamous cell carcinoma subtypes. Increased mCAs and mChrY losses were observed in smokers, with notable racial differences.

Conclusions:

  • Established a significant link between mosaic chromosomal alterations in white blood cells and an elevated risk of lung cancer.
  • Highlighted copy-neutral loss of heterozygosity as a key driver of this association.
  • Indicated potential roles of smoking and race in mCA prevalence and lung cancer risk.