Whole exome sequencing and MicroRNA profiling of lung adenocarcinoma identified risk prediction features for tumors at stage I and its substages

Hao Ho; Sung-Liang Yu; Hsuan-Yu Chen; Shin-Sheng Yuan; Kang-Yi Su; Yi-Chiung Hsu; Chung-Ping Hsu; Cheng-Yen Chuang; Ya-Hsuan Chang; Yu-Cheng Li; Chiou-Ling Cheng; Gee-Chen Chang; Pan-Chyr Yang; Ker-Chau Li

doi:10.1016/j.lungcan.2023.107352

Whole exome sequencing and MicroRNA profiling of lung adenocarcinoma identified risk prediction features for tumors at stage I and its substages

Lung Cancer. 2023 Oct:184:107352. doi: 10.1016/j.lungcan.2023.107352. Epub 2023 Aug 20.

Authors

Affiliations

¹ Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
² Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan; Institute of Medical Device and Imaging, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
³ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁴ Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan.
⁵ Division of Thoracic Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
⁶ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁷ Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan. Electronic address: cshy1888@csh.org.tw.
⁸ Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: pcyang@ntu.edu.tw.
⁹ Institute of Statistical Science, Academia Sinica, Taipei, Taiwan; Department of Statistics, University of California Los Angeles, Los Angeles, CA. Electronic address: kcli@stat.sinica.edu.tw.

PMID: 37657238
DOI: 10.1016/j.lungcan.2023.107352

Abstract

Objectives: About 20% of stage I lung adenocarcinoma (LUAD) patients suffer a relapse after surgical resection. While finer substages have been defined and refined in the AJCC staging system, clinical investigations on the tumor molecular landscape are lacking.

Materials and methods: We performed whole exome sequencing, DNA copy number and microRNA profiling on paired tumor-normal samples from a cohort of 113 treatment-naïve stage I Taiwanese LUAD patients. We searched for molecular features associated with relapse-free survival (RFS) of stage I or its substages and validated the findings with an independent Caucasian LUAD cohort.

Results: We found sixteen nonsynonymous mutations harbored at EGFR, KRAS, TP53, CTNNB1 and six other genes associated with poor RFS in a dose-dependent manner via variant allele fraction (VAF). An index, maxVAF, was constructed to quantify the overall mutation load from genes other than EGFR. High maxVAF scores discriminated a small group of high-risk LUAD at stage I (median RFS: 4.5 versus 69.5 months; HR = 10.5, 95% CI = 4.22-26.12, P < 0.001). At the substage level, higher risk was found for patients with high maxVAF or high miR-31; IA (median RFS: 32.1 versus 122.8 months, P = 0.005) and IB (median RFS: 7.1 versus 26.2, P = 0.049). MicroRNAs, miR-182, miR-183 and miR-196a were found correlated with EGFR mutation and poor RFS in stage IB patients.

Conclusion: Distinctive features of somatic gene mutation and microRNA expression of stage I LUAD are characterized to complement the survival prognosis by substaging. The findings open up more options for precision management of stage I LUAD patients.

Keywords: MicroRNA expression; Relapse risk prediction; Somatic mutation; Stage I lung adenocarcinomas.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung* / genetics
ErbB Receptors / genetics
Exome Sequencing
Humans
Lung Neoplasms* / genetics
MicroRNAs* / genetics

Substances

MicroRNAs
ErbB Receptors