The correlations of tumor mutational burden among single-region tissue, multi-region tissues and blood in non-small cell lung cancer

Yaxiong Zhang,Zhesheng Wen,Qiufan Zheng,Junye Wang,Xin Wang,Huaqiang Zhou,Shen Zhao,Wenfeng Fang,Shaodong Hong,Hao Long,Xi Chen,Hao‐Xian Yang ,Xin Yi,Yuanyuan Zhao,Xuefeng Xia,Aiwei Wu,Yanfang Guan,Zhonghan Zhang,Jie Zhan ,Yuxiang Ma,Hongyun Zhao,Yunpeng Yang,Lianpeng Chang,Ting Zhou,Hong Yang,Lanjun Zhang,Yan Huang,Xue Hou,Gang Chen,Pei Hui ,Ningning Zhou,Li Zhang

doi:10.1186/s40425-019-0581-5

Abstract

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.

Highlights

Tumor mutational burden (TMB) is emerging as a practical biomarker for predicting the response of immune checkpoint inhibitors (ICIs) [1]
Multi-region tissue TMB (tTMB) was calculated with non-repetitive mutations from all regions per megabase. blood TMB (bTMB) was analyzed with tumor-derived mutations from circulating tumor DNA (ctDNA)
epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) showed significantly lower multi-region tTMB than those in kirsten rat sarcoma viral oncogene (KRAS)-mutant LUAD and EGFR&KRAS-wild-type LUAD (Additional file 3: Figure S2). 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) (Fig. 1a). It showed extremely high specificity (100%) but relatively low sensitivity (43%) when using bTMB to define TMB-high patients, while most false-negative predictions were in early-stage (I-II) patients (Fig. 1b)

Summary

Introduction

Tumor mutational burden (TMB) is emerging as a practical biomarker for predicting the response of immune checkpoint inhibitors (ICIs) [1]. Non-small cell lung cancer (NSCLC) patients with higher tissue TMB (tTMB) or blood TMB (bTMB) levels are associated with better efficacy of ICIs [2, 3]. The correlations of single-region tTMB, multi-region tTMB and bTMB remain to be determined. Whether intratumor heterogeneity (ITH) has impact on TMB should be clarified

Methods

Results

Discussion

Conclusion