The correlations of tumor mutational burden among single-region tissue, multi-region tissues and blood in non-small cell lung cancer
The correlations of tumor mutational burden among single-region tissue, multi-region tissues and blood in non-small cell lung cancer
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非小细胞肺癌单区域组织、多区域组织和血液肿瘤突变负荷的相关性
DOI：
10.1186/s40425-019-0581-5
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发表时间：
2019-04-03
影响因子：
10.9
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
在非小细胞肺癌（NSCLC）患者中，高水平的组织肿瘤突变负荷（tTMB）或血液TMB （bTMB）与更好的免疫治疗应答相关。然而，单区域tTMB、多区域tTMB和bTMB的相关性仍有待确定。此外，肿瘤内异质性（ITH）是否对TMB有影响还有待明确。我们收集了32例手术NSCLC患者的多区域肿瘤组织，并通过1021基因面板测序评估了单区域tTMB、多区域tTMB和bTMB。bbb9突变/Mb的TMB为高。此外，我们使用tTMB折叠变化来评估登记区域数量对tTMB的影响。我们发现，单区tTMB和bTMB与多区tTMB均表现出较强的相关性，但前者相关性更强（Pearson r=0.94， P=2E-84; Pearson r=0.47， P=0.0067）。当使用bTMB来定义tmb高患者时，它显示出极高的特异性（100%）但低灵敏度（43%），而大多数假阴性预测发生在早期患者。与单一区域相比，我们发现如果考虑多区域，tTMB折叠变化显著增强。然而，当被纳入的区域数量大于3个时，其tTMB倍变化的增加不显著。此外，ith -高患者的tTMB折叠变化明显高于ith -低患者（2.32 vs. 1.02， P=8.879e-05）。高th组tTMB水平（tTMB低到tTMB高）的转换率数值上高于低th组（16.67%比3.84%）。综上所述，与bTMB相比，单区域tTMB与多区域tTMB具有更强的相关性。ITH对tTMB有影响，尤其是高水平ITH患者。
High-level tissue tumor mutational burden (tTMB) or blood TMB (bTMB) are associated with better response of immunotherapy in non-small cell lung cancer (NSCLC) patients. However, the correlations of single-region tTMB, multi-region tTMB and bTMB remain to be determined. Moreover, whether intratumor heterogeneity (ITH) has impact on TMB should be clarified. We collected multi-region tumor tissues with matched blood from 32 operative NSCLC and evaluated single-region tTMB, multi-region tTMB and bTMB through a 1021-gene panel sequencing. TMB of >9 mutations/Mb was classified as high. Besides, we used tTMB fold-change to evaluate the influence of the enrolled region number on tTMB. We found both of single-region tTMB and bTMB showed strong correlations with multi-region tTMB, while the former correlated better (Pearson r=0.94, P=2E-84; Pearson r=0.47, P=0.0067). It showed extremely high specificity (100%) but low sensitivity (43%) when using bTMB to define TMB-high patients, while most false-negative predictions were in early-stage patients. Compared to single region, we found significantly enhanced tTMB fold-change if taking multi-regions for consideration. However, it showed insignificant tTMB fold-change increase if the included regions' number more than three. Moreover, ITH-high patients had significantly higher tTMB fold-change compared with ITH-low patients (2.32 vs. 1.02, P=8.879e-05). The conversion rate of tTMB level (tTMB-low to tTMB-high) was numerically higher in ITH-high group than that in ITH-low group (16.67% vs. 3.84%). In summary, single-region tTMB has stronger correlation with multi-region tTMB compared with bTMB. ITH has an impact on tTMB, especially in high-level ITH patients.