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Co-occurring genetic alterations and primary EGFR T790M mutations detected by NGS in pre-TKI-treated NSCLCs.

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.

Authors+Show Affiliations

Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.Department of Pathology, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing, China.Beijing Novogene Bioinformatics Technology Co., Ltd., Beijing, China.Beijing Novogene Bioinformatics Technology Co., Ltd., Beijing, China.Department of Pathology, Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, China.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.Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, 127 Dongming Road, Zhengzhou, 450003, China.Medical Affairs Department, Pfizer Oncology, Shanghai, China.Medical Affairs Department, Pfizer Oncology, Shanghai, China.Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, 127 Dongming Road, Zhengzhou, 450003, China. majie_fzbl@163.com.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31696302

Citation

Tang, Yuan, et al. "Co-occurring Genetic Alterations and Primary EGFR T790M Mutations Detected By NGS in pre-TKI-treated NSCLCs." Journal of Cancer Research and Clinical Oncology, 2019.
Tang Y, Che N, Yu Y, et al. Co-occurring genetic alterations and primary EGFR T790M mutations detected by NGS in pre-TKI-treated NSCLCs. J Cancer Res Clin Oncol. 2019.
Tang, Y., Che, N., Yu, Y., Gao, Y., Shi, H., Feng, Q., ... Lin, D. (2019). Co-occurring genetic alterations and primary EGFR T790M mutations detected by NGS in pre-TKI-treated NSCLCs. Journal of Cancer Research and Clinical Oncology, doi:10.1007/s00432-019-03065-0.
Tang Y, et al. Co-occurring Genetic Alterations and Primary EGFR T790M Mutations Detected By NGS in pre-TKI-treated NSCLCs. J Cancer Res Clin Oncol. 2019 Nov 6; PubMed PMID: 31696302.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Co-occurring genetic alterations and primary EGFR T790M mutations detected by NGS in pre-TKI-treated NSCLCs. AU - Tang,Yuan, AU - Che,Nanying, AU - Yu,Yang, AU - Gao,Yun, AU - Shi,Huaiyin, AU - Feng,Qin, AU - Wei,Bing, AU - Ma,Liheng, AU - Gao,Min, AU - Ma,Jie, AU - Lin,Dongmei, Y1 - 2019/11/06/ PY - 2019/05/30/received PY - 2019/10/23/accepted PY - 2019/11/8/entrez PY - 2019/11/7/pubmed PY - 2019/11/7/medline KW - Co-occurring genetic alterations KW - Next-generation sequencing KW - Non-small cell lung cancer JF - Journal of cancer research and clinical oncology JO - J. Cancer Res. Clin. Oncol. N2 - 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. SN - 1432-1335 UR - https://www.unboundmedicine.com/medline/citation/31696302/Co-occurring_genetic_alterations_and_primary_EGFR_T790M_mutations_detected_by_NGS_in_pre-TKI-treated_NSCLCs L2 - https://dx.doi.org/10.1007/s00432-019-03065-0 DB - PRIME DP - Unbound Medicine ER -