Integrated analysis of genomic alterations of Chinese lung adenocarcinoma with micropapillary component.

Abstract

e15130 Background: Lung adenocarcinoma (LADC) with micropapillary component (MPC) is a special pathological subtype of LADC, which poses higher invasive with poor prognosis, regardless of proportion of MPC. The effectiveness of molecular targeted therapy in MPC-LADC patients is still being explored without sufficient clinical evidence. Herein, we comprehensive analyzed the genetic alterations of MPC-LADC in order to find effective potential drug-target genes and guide new therapeutic strategies. Methods: We enrolled 31 MPC-LADC patients at Department of Thoracic Surgery, The Affiliated Hospital of Qingdao University from January 2019 to December 2020, and also randomly selected 89 non-MPC-LADC patients as a reference cohort. FFPE or fresh tumors and matched blood samples were performed for NGS-based target panel detection of at least 420 genes (range 420-638 genes), and we analyzed the genomic alterations of the genes with intersection in the above panels sequencing. Results: In our MPC-LADC cohort, the proportion of micropapillary component in 31 tumors were: 5 cases with MPC < 5%, 13 cases with MPC 5% - 20%, 10 cases with MPC ≥20% and other 3 cases unclear. The most frequently mutant genes were EGFR (61.3%, 19/31), TP53 (41.9%, 13/31), ALK (19.4%, 6/31), CTNNB1 (16.1%, 5/31), KRAS (12.9%, 4/31) and SMAD4 (12.9%, 4/31). Moreover, 90.3% (28/31) patients harbored genomic alterations in RTK/RAS/MAPK pathway, 54.8% (17/31) in cell-cycle pathway, 38.7% (12/31) in Wnt pathway, and 19.4% (6/31) in PI3K/AKT/mTOR pathway. Notably, the median age of patients with ALK fusions were younger than wild-type patients (53 vs 60 years, p < 0.05). Patients with KRAS mutations had larger tumor sizes than wild-type patients (Median: 3.4 vs 2.2 cm, p < 0.05), and their lesions are more prone to vascular invasion (p < 0.05). Compared with the reference group of non-MPC-LADC patients, three mutant genes were significantly enriched in MPC-LADC group, namely, CTNNB1 (16.1% vs 1.1%, p < 0.01), ALK (16.1% vs 2.2%, p < 0.05) and SMAD4 (12.9% vs 2.2%, p < 0.05). Finally, we obtained the date of micropapillary lung adenocarcinoma in Memorial Sloan-Kettering Cancer Center (MSK) from cBioPortal database, and survival outcome analysis displayed that EGFR mutations were significantly associated with poor overall survival (OS) (p < 0.05). Conclusions: In this study, we comprehensive revealed the genomic alterations of Chinese MPC-LADC patients and their association with clinicopathological characteristic. Several MPC-enriched genes including EGFR, ALK, KRAS, CTNNB1 and SMAD4 were identified which may be potential genetic drivers of micropapillary lung tumors and could help us to reveal distinct therapeutic avenues of MPC-LADC.