Low OLFM1 and BMP6 Expression Predicts Recurrence in Early-Stage Nonsquamous NSCLC with Pure Solid Tumor Appearance

Although pathologic stage I (pStage I) non-small cell lung cancer (NSCLC) has a good prognosis, some patients experience disease recurrence. Identification of prognostic markers for pStage I NSCLC may facilitate personalized perioperative treatment by expanding the candidates for adjuvant treatment. Patients with NSCLC with ground-glass opacity have excellent survival outcomes. Therefore, in this study, we explored prognostic biomarkers in pure solid nonsquamous NSCLC. We focused on nonsquamous NSCLC because the gene expression status is distinct from that of squamous cell carcinomas. RNA sequencing was performed on frozen tumor specimens from 33 patients with nonsquamous NSCLC with disease recurrence (recurrence group) and 33 counterparts (control group) extracted from patients without disease recurrence using propensity score matching (cohort 1). The candidate genes were further refined using an independent real-world cohort 2a (N = 125) and validated in The Cancer Genome Atlas cohort. Through the analysis of cohort 1 and cohort 2a, we found that low expression of six genes (BMP6, KCNK3, NFASC, OLFM1, PEG3, and TNXB) was associated with disease recurrence. The prognostic impact of the six genes was confirmed using The Cancer Genome Atlas lung adenocarcinoma database. Multivariable proportional hazard analysis using the cohort 2a dataset revealed that the combination of BMP6 and OLFM1 status predicted recurrence-free survival. In conclusion, we found that low BMP6/OLFM1 gene status is a potential biomarker to identify patients with high-risk pStage I pure solid nonsquamous NSCLC after pulmonary resection.

The identification of subgroups with a high risk of disease recurrence among patients with NSCLC with pStage I is an important clinical issue. We explored genetic factors in patients with pStage I NSCLC with a high-risk clinical feature and identified low expression of OLFM1 and BMP6 genes as candidate biomarkers. Clinical application of these biomarkers, together with others, will open an opportunity to administer adequate adjuvant treatment for these high-risk patients.