Intratumor heterogeneity comparison among different subtypes of non-small-cell lung cancer through multi-region tissue and matched ctDNA sequencing
Intratumor heterogeneity comparison among different subtypes of non-small-cell lung cancer through multi-region tissue and matched ctDNA sequencing
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通过多区域组织和匹配的ctDNA测序比较非小细胞肺癌不同亚型的瘤内异质性
DOI：
10.1186/s12943-019-0939-9
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发表时间：
2019-01-09
期刊：
影响因子：
37.3
通讯作者：
Zhang, Li
中科院分区：
文献类型：
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作者：
Zhang, Yaxiong;Chang, Lianpeng;Zhang, Li
了解不同非小细胞肺癌（NSCLC）亚型之间的肿瘤内异质性（ITH）是必要的。循环肿瘤DNA （ctDNA）谱是否可以代表这些ITH仍然是一个悬而未决的问题。我们对32例手术NSCLC进行了181例多区域肿瘤组织测序和匹配ctDNA测序，以比较不同NSCLC亚型（包括egfr -突变型肺腺癌（LUAD）、kras -突变型LUAD、egfr & kras -野生型LUAD和肺鳞状细胞癌（LUSC））的ITH，并研究ctDNA在ITH分析中的潜在价值。ITH用ITH指数（ITHi）来评价。如果所有组织区域共有体细胞遗传改变，则定义为主干突变。否则称为分支突变。如果肿瘤主干突变较少，ITHi会更高。我们发现egfr突变型LUAD的ITHi显著高于kras突变型LUAD/野生型LUAD (P=0.03)，数值上高于LUSC。对于主干突变，总体而言，驱动突变的比例高于乘客突变（60%比40%，P=0.0023），特别是在egfr突变体LUAD中（86%比14%，P=0.0004），而在kras突变体LUAD中相反（40%比60%，P=0.18）。对于分支突变，每种NSCLC亚型中驱动突变和乘客突变的比例相似。ctDNA分析显示，在所有NSCLC亚型中，肿瘤源性主干和分支突变的检测不理想（43%对23%，P=4.53e-6）。综上所述，egfr突变LUAD的ITH高于其他NSCLC亚型，为进一步了解不同NSCLC亚型之间的肿瘤发生机制提供了依据。此外，ctDNA可能不是一个合适的方法来反映ITH。
Understanding of intratumor heterogeneity (ITH) among different non-small cell lung cancer (NSCLC) subtypes is necessary. Whether circulating tumor DNA (ctDNA) profile could represent these ITH is still an open question. We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis. ITH is evaluated by ITH index (ITHi). If the somatic genetic alteration is shared by all the tissue regions, it is defined as trunk mutation. Otherwise, it is called branch mutation. The ITHi will be higher, if the tumor has less trunk mutations. We found EGFR-mutant LUAD showed significantly higher ITHi than KRAS-mutant LUAD/wild-type LUAD (P=0.03) and numerically higher ITH than LUSC. For trunk mutations, driver mutations were identified at a higher proportion than passenger mutations (60% vs. 40%, P=0.0023) in overall, especially in EGFR-mutant LUAD (86% vs. 14%, P=0.0004), while it was opposite in KRAS-mutant LUAD (40% vs. 60%, P=0.18). For branch mutations, the proportions of driver mutations and passenger mutations were similar for each NSCLC subtype. ctDNA analysis showed unsatisfactory detections of tumor-derived trunk and branch mutations (43% vs. 23%, P=4.53e-6) among all NSCLC subtypes. In summary, EGFR-mutant LUAD has the highest ITH than other NSCLC subtypes, offering further understanding of tumorigenesis mechanisms among different NSCLC subtypes. Besides, ctDNA maybe not an appropriate method to reflect ITH.