Yuan Tang1, Nanying Che2, Yang Yu3, Yun Gao3, Huaiyin Shi4, Qin Feng5, Bing Wei6, Liheng Ma7, Min Gao7, Jie Ma8, Dongmei Lin9. 1. Department of Pathology, West China Hospital, Sichuan University, Chengdu, China. 2. Department of Pathology, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing, China. 3. Beijing Novogene Bioinformatics Technology Co., Ltd., Beijing, China. 4. Department of Pathology, Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, China. 5. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Fucheng Road No. 52, Haidian District, Beijing, 100142, China. 6. Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, 127 Dongming Road, Zhengzhou, 450003, China. 7. Medical Affairs Department, Pfizer Oncology, Shanghai, China. 8. Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, 127 Dongming Road, Zhengzhou, 450003, China. majie_fzbl@163.com. 9. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Fucheng Road No. 52, Haidian District, Beijing, 100142, China. Dongm_lin@126.com.
Abstract
INTRODUCTION: Next-generation sequencing (NGS)-based assays to understand various mutations and co-occurrence of genomic alterations in non-small cell lung cancer (NSCLC) have enabled understanding of treatment impact on clinical outcomes. METHODS: This retrospective study was conducted in 1353 formalin-fixed paraffin-embedded (FFPE) tissues from surgically resected, pre-TKI-treated NSCLC patients with identified gene alterations. Genomic DNA and RNA extraction was followed by NGS library preparation and sequencing using the Ion Ampliseq Colon and Lung Cancer Gene Panel V2 and the AmpliSeq RNA Lung Cancer Research Fusion Panel. RESULTS: A total of 2328 alterations in 25 genes were detected from the 1293 patients. DNA mutations and RNA fusions co-occurred in 27 patients with TP53 being the most common co-occurring DNA mutation (43.8%) with concurrent ALK fusions. Analysis of the 975 patients with EGFR mutations revealed that the incidence of dual EGFR L858R/T790M mutations was higher compared to EGFR 19del/T790M, and the mean allele fraction (MAF) of T790M was lower compared to 19del in dual EGFR 19del/T790M patients. CONCLUSION: NSCLC patients represented genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways. This diverse mutational profile may have key clinical and research implications for understanding the variability of treatment outcome in pre-TKI-treated NSCLC population. The differences in the MAF of EGFR T790M may determine different responses to TKI therapy in patients harboring dual mutations.
INTRODUCTION: Next-generation sequencing (NGS)-based assays to understand various mutations and co-occurrence of genomic alterations in non-small cell lung cancer (NSCLC) have enabled understanding of treatment impact on clinical outcomes. METHODS: This retrospective study was conducted in 1353 formalin-fixed paraffin-embedded (FFPE) tissues from surgically resected, pre-TKI-treated NSCLCpatients with identified gene alterations. Genomic DNA and RNA extraction was followed by NGS library preparation and sequencing using the Ion Ampliseq Colon and Lung Cancer Gene Panel V2 and the AmpliSeq RNA Lung Cancer Research Fusion Panel. RESULTS: A total of 2328 alterations in 25 genes were detected from the 1293 patients. DNA mutations and RNA fusions co-occurred in 27 patients with TP53 being the most common co-occurring DNA mutation (43.8%) with concurrent ALK fusions. Analysis of the 975 patients with EGFR mutations revealed that the incidence of dual EGFR L858R/T790M mutations was higher compared to EGFR 19del/T790M, and the mean allele fraction (MAF) of T790M was lower compared to 19del in dual EGFR 19del/T790Mpatients. CONCLUSION:NSCLCpatients represented genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways. This diverse mutational profile may have key clinical and research implications for understanding the variability of treatment outcome in pre-TKI-treated NSCLC population. The differences in the MAF of EGFRT790M may determine different responses to TKI therapy in patients harboring dual mutations.
Entities:
Keywords:
Co-occurring genetic alterations; Next-generation sequencing; Non-small cell lung cancer
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