Yue Zhao1,2,3,4, Yunjian Pan1,2,3,4, Chao Cheng1,2,3,4, Difan Zheng1,2,3,4, Yang Zhang1,2,3,4, Zhendong Gao1,2,3,4, Fangqiu Fu1,2,3,4, Hang Li1,2,3,4, Shanbo Zheng1,2,3,4, Lingdun Zhuge1,2,3,4, Hengyu Mao1,2,3,4, Muyu Kuang1,2,3,4, Xiaoting Tao1,2,3,4, Yizhou Peng1,2,3,4, Hong Hu1,2,3,4, Jiaqing Xiang1,2,3,4, Yuan Li4,5, Yihua Sun1,2,3,4, Haiquan Chen6,7,8,9. 1. Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China. 2. Institute of Thoracic Oncology, Fudan University, Shanghai, 200032, China. 3. State Key Laboratory of Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, China. 4. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. 5. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. 6. Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China. hqchen1@yahoo.com. 7. Institute of Thoracic Oncology, Fudan University, Shanghai, 200032, China. hqchen1@yahoo.com. 8. State Key Laboratory of Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, China. hqchen1@yahoo.com. 9. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. hqchen1@yahoo.com.
Abstract
INTRODUCTION: EGFR mutations occur most frequently in patients with lung adenocarcinoma in East Asia. However, the prognostic and therapeutic impact of co-mutational status of EGFR and tumor suppressor genes is not fully understood. This study aims to provide a deeper understanding of lung adenocarcinoma patients with co-mutation of EGFR and tumor suppressor genes. METHODS: From November 2009 to May 2016, 675 patients with lung adenocarcinoma who underwent complete surgery were included in this study. Samples were collected and pathologically examined. Whole-exome sequencing was performed on 197 samples, while direct sequencing of major driver genes, including EGFR, KRAS, ERBB2 and BRAF and Ion-torrent targeted sequencing of tumor suppressor genes, including TP53, KEAP1, MGA, NF1, RB1, SMARCA4 and STK11, were performed on 478 samples. Tumor mutational burden was calculated and survival analyses were performed. RESULTS: The frequency of EGFR and TP53 mutation was 409 (60.6%) and 215 (31.9%), respectively. Co-mutation of EGFR and TP53 occured in 151 patients (22.4%), while co-mutation of EGFR and at least one tumor suppressor gene occured in 184 patients (27.3%). Compared with patients with only EGFR mutations, patients with co-mutations of EGFR and TP53 had a higher tumor mutational burden (p = 0.007) and worse recurrence-free survival (p = 0.010), while patients with co-mutations of EGFR and at least one tumor suppressor gene had a higher tumor mutational burden (p = 0.007), worse recurrence-free survival (p = 0.016) and worse overall survival (p = 0.018). CONCLUSIONS: Lung adenocarcinoma patients harboring EGFR and co-mutational tumor suppressor genes should be regarded as a unique subgroup.
INTRODUCTION:EGFR mutations occur most frequently in patients with lung adenocarcinoma in East Asia. However, the prognostic and therapeutic impact of co-mutational status of EGFR and tumor suppressor genes is not fully understood. This study aims to provide a deeper understanding of lung adenocarcinomapatients with co-mutation of EGFR and tumor suppressor genes. METHODS: From November 2009 to May 2016, 675 patients with lung adenocarcinoma who underwent complete surgery were included in this study. Samples were collected and pathologically examined. Whole-exome sequencing was performed on 197 samples, while direct sequencing of major driver genes, including EGFR, KRAS, ERBB2 and BRAF and Ion-torrent targeted sequencing of tumor suppressor genes, including TP53, KEAP1, MGA, NF1, RB1, SMARCA4 and STK11, were performed on 478 samples. Tumor mutational burden was calculated and survival analyses were performed. RESULTS: The frequency of EGFR and TP53 mutation was 409 (60.6%) and 215 (31.9%), respectively. Co-mutation of EGFR and TP53 occured in 151 patients (22.4%), while co-mutation of EGFR and at least one tumor suppressor gene occured in 184 patients (27.3%). Compared with patients with only EGFR mutations, patients with co-mutations of EGFR and TP53 had a higher tumor mutational burden (p = 0.007) and worse recurrence-free survival (p = 0.010), while patients with co-mutations of EGFR and at least one tumor suppressor gene had a higher tumor mutational burden (p = 0.007), worse recurrence-free survival (p = 0.016) and worse overall survival (p = 0.018). CONCLUSIONS:Lung adenocarcinomapatients harboring EGFR and co-mutational tumor suppressor genes should be regarded as a unique subgroup.