Recurrence-associated gene signature in patients with stage I non-small-cell lung cancer

Su Han Cho,Dae Ho Lee,Sang-We Kim,Shinkyo Yoon,Kwoneel Kim

doi:10.1038/s41598-021-99197-w

Su Han Cho, Dae Ho Lee + Show 3 more

Open Access

https://doi.org/10.1038/s41598-021-99197-w

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Abstract

Recurrent gene mutations and fusions in cancer patients are likely to be associated with cancer progression or recurrence by Vogelstein et al. (Science (80-)340, 1546–1558 (2013)). In this study, we investigated gene mutations and fusions that recurrently occurred in early-stage cancer patients with stage I non-small-cell cancer (NSCLC). Targeted exome sequencing was performed to profile the variants and confirmed their fidelity at the gene and pathway levels through comparison with data for stage I lung cancer patients, which was obtained from The Cancer Genome Atlas (TCGA). Next, we identified prognostic gene mutations (ATR, ERBB3, KDR, and MUC6), fusions (GOPC-ROS1 and NTRK1-SH2D2A), and VEGF signaling pathway associated with cancer recurrence. To infer the functional implication of the recurrent variants in early-stage cancers, the extent of their selection pattern was investigated, and they were shown to be under positive selection, implying a selective advantage for cancer progression. Specifically, high selection scores were observed in the variants with significantly high risks for recurrence. Taken together, the results of this study enabled us to identify recurrent gene mutations and fusions in a stage I NSCLC cohort and to demonstrate positive selection, which had implications regarding cancer recurrence.

Highlights

Lung cancer remains the leading cause of cancer death worldwide
Despite the limited resolution of targeted sequencing, this method was employed successfully to identify the genes reported in the previous study for a large lung cancer cohort (TCGA); these genes were KDR, BRCA1, BRCA2, EGFR, ERBB2, and TP53 for mutations and ALK-EML4 and KIF5B-RET for gene fusions
These gene mutations and fusions were compared to the The Cancer Genome Atlas (TCGA) lung cancer cohort according to stage

Summary

Results

Higher selective scores in recurrently mutated genes were observed to be more significant for stage I than stage IV, regardless of the measurement method in the permutation test (Supplementary Fig. 3) Taken together, these results indicated that mutations and fusions in the early tumor stage tended to be more subject to positive selection so that they have more functional implications in cancer progression. In our study of tumor recurrence, a significant correlation with RFS was observed in gene mutations (ATR, ERBB3, KDR, and MUC6) and fusions (GOPCROS1 and NTRK1-SH2D2A) This significant RFS benefit with two gene mutations (ERBB3 and KDR) was only observed in our early-stage cohort when compared with the TCGA stage IV cohort (Supplementary Fig. 5). These previous studies describing the variants in our cohort have implications of oncogenic relevance to lung cancer recurrence

Discussion

B: Selection score by Bayesian model M

Materials and methods