Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
J Exp Clin Cancer Res. 2022 May 11;41(1):172. doi: 10.1186/s13046-022-02361-x.
Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy.
In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors.
We observed heterogeneous mutation, methylation, and T cell patterns across distinct metastases. Only TP53 mutation was detected in all tumors suggesting an early event while other cancer gene mutations were later events which may have followed subclonal diversification. A set of prevalent T cell clonotypes were completely excluded from left-side thoracic tumors indicating distinct T cell repertoire profiles between left-side and non left-side thoracic tumors. Though a limited number of predicted neoantigens were shared, these were associated with homology of the T cell repertoire across metastases. Lastly, ratio of methylated neoantigen coding mutations was negatively associated with T-cell density, richness and clonality, suggesting neoantigen methylation may partially drive immunosuppression.
Our study demonstrates heterogeneous genomic and T cell profiles across synchronous metastases and how restriction of unique T cell clonotypes within an individual may differentially shape the genomic and epigenomic landscapes of synchronous lung metastases.
肺癌是癌症死亡的主要原因，部分原因是其广泛的异质性。由于无法同时获得未经多次先前治疗改变的同步转移灶的组织，因此对肿瘤间异质性的分析受到限制。
为了研究一名从未吸烟的 32 岁女性左肺原发性晚期肺腺癌（LUAD）罕见尸检病例中基因组、表观基因组和 T 细胞受体（TCR）多样性之间的关系，我们进行了全外显子组测序（WES）、DNA 甲基化和 TCR 测序，以描绘一个原发性和 19 个同步转移瘤的免疫基因组图谱。
我们观察到不同转移灶之间存在异质性的突变、甲基化和 T 细胞模式。只有 TP53 突变在所有肿瘤中均被检测到，提示为早期事件，而其他癌症基因突变则为晚期事件，可能是亚克隆多样化的结果。一组常见的 T 细胞克隆型完全排除在左侧胸腔肿瘤之外，表明左侧和非左侧胸腔肿瘤之间存在不同的 T 细胞受体谱。尽管共享的预测新抗原数量有限，但这些与转移灶之间的 T 细胞受体同源性相关。最后，甲基化新抗原编码突变的比例与 T 细胞密度、丰富度和克隆性呈负相关，提示新抗原甲基化可能部分导致免疫抑制。
我们的研究表明，同步转移灶之间存在异质性的基因组和 T 细胞谱，以及个体内独特的 T 细胞克隆型的限制如何不同地塑造同步肺转移灶的基因组和表观基因组景观。
