Next-Generation Sequencing Reveals High Uncommon EGFR Mutations and Tumour Mutation Burden in a Subgroup of Lung Cancer Patients

Xuanwei County in Southwest China shows the highest incidence and mortality rate of lung cancer in China. Although studies have reported distinct clinical characteristics of patients from Xuanwei, the molecular features of these patients with non-small cell lung cancer (NSCLC) remain unclear. Here, we comprehensively characterised such cases using next-generation sequencing (NGS). Formalin-fixed, paraffin-embedded tumour samples from 146 patients from Xuanwei with NSCLC were collected for an NGS-based target panel assay; their features were compared with those of reference Chinese and The Cancer Genome Atlas (TCGA) cohorts. Uncommon EGFR mutations, defined as mutations other than L858R, exon 19del, exon 20ins, and T790M, were the predominant type of EGFR mutations in the Xuanwei cohort. Patients harbouring uncommon EGFR mutations were more likely to have a family history of cancer (p = 0.048). A higher frequency of KRAS mutations and lower frequency of rearrangement alterations were observed in the Xuanwei cohort (p < 0.001). Patients from Xuanwei showed a significantly higher tumour mutation burden than the reference Chinese and TCGA cohorts (p < 0.001). Our data indicates that patients from Xuanwei with NSCLC harbouring G719X/S768I co-mutations may benefit from treatment with EGFR-tyrosine kinase inhibitors. Our comprehensive molecular profiling revealed unique genomic features of patients from Xuanwei with NSCLC, highlighting the potential for improvement in targeted therapy and immunotherapy.

[1]  Liming Li,et al.  Establishment of reference intervals of ten commonly used clinical chemistry analytes: a real-world study in China. , 2021, Biomarkers in Medicine.

[2]  A. Jemal,et al.  Cancer statistics, 2020 , 2020, CA: a cancer journal for clinicians.

[3]  J. Ahn,et al.  Osimertinib for Patients With Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase II Trial (KCSG-LU15-09). , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Y. Liao,et al.  The characteristics of lung cancer in Xuanwei County: A review of differentially expressed genes and noncoding RNAs on cell proliferation and migration. , 2019, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[5]  J. Desai,et al.  The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity , 2019, Nature.

[6]  Yuwei Cheng,et al.  An Accurate and Comprehensive Clinical Sequencing Assay for Cancer Targeted and Immunotherapies. , 2019, The oncologist.

[7]  Xin Wang,et al.  The immune response‐related mutational signatures and driver genes in non‐small‐cell lung cancer , 2019, Cancer science.

[8]  Yu-An Dong,et al.  Genomic Signature of Driver Genes Identified by Target Next-Generation Sequencing in Chinese Non-Small Cell Lung Cancer. , 2019, The oncologist.

[9]  Haifeng Song,et al.  Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients , 2019, Journal of Hematology & Oncology.

[10]  Wanqing Chen,et al.  Epidemiology of lung cancer in China , 2018, Thoracic cancer.

[11]  B. Guleng,et al.  Germline and somatic variations influence the somatic mutational signatures of esophageal squamous cell carcinomas in a Chinese population , 2018, BMC genomics.

[12]  J. Szustakowski,et al.  Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden , 2018, The New England journal of medicine.

[13]  J. Shih,et al.  Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer , 2018, Molecular Cancer.

[14]  A. Fernández-Villar,et al.  Environmental tobacco smoke exposure and EGFR and ALK alterations in never smokers' lung cancer. Results from the LCRINS study. , 2017, Cancer letters.

[15]  Wei-Chih Liao,et al.  Comparing the effects of afatinib with gefitinib or Erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations. , 2017, Lung cancer.

[16]  M. Tsao,et al.  Uncommon EGFR mutations in advanced non-small cell lung cancer. , 2017, Lung cancer.

[17]  M. Socinski,et al.  First‐Line Nivolumab in Stage IV or Recurrent Non–Small‐Cell Lung Cancer , 2017, The New England journal of medicine.

[18]  B. Han,et al.  EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon EGFR mutations: A real-world study in China. , 2016, Lung cancer.

[19]  Chandra Sekhar Pedamallu,et al.  Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas , 2016, Nature Genetics.

[20]  Lijuan Ye,et al.  Distinct epithelial growth factor receptor mutation profile in non-small-cell lung cancer patients from the Xuanwei area of China , 2016, Molecular and clinical oncology.

[21]  B. Taylor,et al.  deconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution , 2016, Genome Biology.

[22]  X. Zou,et al.  The mortality patterns of lung cancer between 1990 and 2013 in Xuanwei, China. , 2015, Lung cancer.

[23]  N. Girard,et al.  The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes. , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[24]  L. Sequist,et al.  Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. , 2015, The Lancet. Oncology.

[25]  Yize Xiao,et al.  The epidemic status and risk factors of lung cancer in Xuanwei City, Yunnan Province, China , 2012, Frontiers of Medicine.

[26]  E. Felip,et al.  Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. , 2012, The Lancet. Oncology.

[27]  S. Toyooka,et al.  Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. , 2010, The Lancet. Oncology.

[28]  Ping Yang,et al.  Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. , 2008, Mayo Clinic proceedings.

[29]  M. Ostland,et al.  Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  Ying Cheng,et al.  Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. , 2018, The Lancet. Oncology.

[31]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.