Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas.
J Thorac Oncol. 2023 Aug;18(8):1003-1016. doi: 10.1016/j.jtho.2023.05.001. Epub 2023 May 5.
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.
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.
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.
Our study established a link between mCAs in white blood cells and increased risk of lung cancer.
在白细胞中检测到的镶嵌性染色体改变（mCAs）代表了一种与 CH 相关体细胞突变相比研究较少的克隆性造血（CH）。最近的一些研究表明，它们与非血液系统癌症，尤其是肺癌之间存在潜在联系。
本研究利用 INTEGRAL-ILCCO 的 OncoArray 研究中的高密度基因分型数据，调查了 mCAs 与肺癌之间的关联。该研究是针对肺癌的最大单基因研究，包含了 18221 例肺癌病例和 14825 例无癌症对照。
我们从这些样本中确定了一系列常染色体 mCAs、ChrX mCAs 和镶嵌性 ChrY（mChrY）缺失。除了女性中 3.6%存在 ChrX mCAs 和男性中 9.6%存在 mChrY 缺失外，还有 4.3%的个体存在常染色体 mCAs。多变量逻辑回归分析表明，在调整了年龄、性别、吸烟状况和种族等关键混杂因素后，白细胞中存在常染色体 mCAs 与肺癌风险增加相关。这种关联主要是由一种特定类型的 mCAs 驱动的：常染色体染色体的非平衡性杂合性缺失。在肺腺癌和鳞状细胞癌这两种主要的组织学亚型中，常染色体非平衡性杂合性缺失与肺癌风险增加之间的关联得到了进一步证实。此外，我们观察到吸烟者中 ChrX mCAs 和 mChrY 缺失的比例明显高于非吸烟者，并且某些类型的 mCA 事件存在种族差异。
本研究确立了白细胞中 mCAs 与肺癌风险增加之间的联系。
