Genomic Features and Prognostic Biomarkers of Chinese Resectable Lung Adenocarcinoma Patients with a Micropapillary Component

Abstract Background Lung adenocarcinoma (LADC) with a micropapillary component (MPC) (LMPC) is an aggressive histologic subtype of lung cancer, with unique pathological features and poor prognosis. Previous studies have characterized the driver mutations in LMPC, however, its comprehensive molecular profile and prognosis-related biomarkers in the Chinese population remain elusive. Methods We retrospectively studied 54 stage I-III LMPC patients who underwent complete resection and the LMPC tumor samples were characterized using broad-panel next-generation sequencing (NGS) of 425 cancer-related genes. The association among clinicopathologic factors, genomic characteristics, and post-operation recurrence risk were then explored. Results When compared with a reference cohort of 113 LADC patients, LMPC exhibited a unique genetic profile, with more diverse targetable mutations, an increased number of oncogenic pathways altered (NPA), and more oncogenic pathway-related alterations. The mutation frequencies of ERBB4 (11.1% vs. 1.8%, P = 0.015), BRAF (9.3% vs. 1.8%, P = 0.037), PIK3CA (14.8% vs. 4.4%, P = 0.029), RPTOR ( P = 0.033), and NOTCH2 ( P = 0.033) were significantly higher in LMPC. Moreover, LMPC patients harbored significantly more alterations in three oncogenic pathways (i.e., PI3K, WNT, and TGF-β) and a significantly increased NPA( P < 0.001). By analyzing the correlations between genetic features and median disease-free survival (mDFS) in stage II-III LMPC patients, SMARCA4 mutations (13.9 months vs. Not reached (NR), P = 0.013), as well as alterations in the SWI/SNF (16.3 months vs.NR, P = 0.003) and NRF2 (17.0 monthsvs.NR, P = 0.046) pathways, were significantly associated with higher postoperative recurrence risk. Furthermore, tumor mutation burden (TMB) was significantly correlated with postoperative DFS, with low TMB patients associating with prolonged mDFS than high TMB patients (NR vs.16.8 months, P = 0.021). Conclusion Our study elucidated the unique genetic features and the associated prognosis in Chinese resectable LMPC patients, and we found several molecular factors, especially TMB, can serve as potential prognostic biomarkers in stage II-III resectable LMPC. This study helps better understand the underlying mechanism and direct treatment decisions of this aggressive cancer subtype.