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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number107352
JournalLung Cancer
Volume184
DOIs
StatePublished - Oct 2023

Keywords

  • MicroRNA expression
  • Relapse risk prediction
  • Somatic mutation
  • Stage I lung adenocarcinomas

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