Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment.

Introduction: Recent studies have indicated that the presence of ground-glass opacity (GGO) components is associated with favorable survival. The purpose of this study was to reveal the prognostic value of GGO components and differences in prognostic factors for part-solid and solid lesions in invasive stage I NSCLC. Methods: The cases of 2010 patients with completely resected invasive pathological stage I NSCLC were reviewed according to the eighth edition of the TNM classification. Patients were categorized into the pure-GGO, part-solid, and solid groups based on consolidation-to-tumor ratio. Cox multivariate proportional hazard analyses were conducted to identify independent prognostic factors in each group. Results: Of the 2010 patients, 146 (7.3%) were in the pure-GGO group, 732 (36.4%) were in the part-solid group, and 1132 (56.3%) were in the solid group. Cox multivariate analyses revealed that GGO absence was a strong independent risk factor for worse recurrence-free survival (p < 0.001). For the pure-GGO group, there was no recurrence in spite of the invasive stage. For the partsolid group, visceral pleural invasion could not predict recurrence-free survival in general (p ¼ 0.514) or in each tumor size group (for tumors size 1 cm, p ¼ 0.664; for tumors size >1 to 2 cm, p ¼ 0.456; for tumors size >2 to 3 cm, p ¼ 0.900; and for tumors size >3 to 4 cm, p ¼ 0.397). For the solid group, adenocarcinoma subtype was not a prognostic factor for recurrence-free survival in general (p ¼ 0.162) or in each tumor size group (for tumors size 2 cm, p ¼ 0.092; for tumors size >2 to 3 cm, p ¼ 0.330; and for tumors size >3 to 4 cm, p ¼ 0.885). Conclusions: The presence of GGO components was a strong predictor in patients with invasive pathological stage I NSCLC. Risk factors were distinct in the part-solid and solid groups. There was no prognostic value of visceral pleural invasion in the part-solid group. Adenocarcinoma subtype did not have prognostic value in the solid group.

Introduction: Multiple oncogene fusions beyond ALK receptor tyrosine kinase (ALK), RET, and ROS1 fusion has been described in lung cancer, especially in lung adenocarcinomas without common oncogenic mutations. Molecular inhibitors have been developed and proved effective for patients whose tumors harbor these novel alterations. Methods: A consecutive series of surgically resected lung adenocarcinomas were collected and profiled using an enrichment strategy to detect nine common oncogenic driver mutations and fusions concerning EGFR, KRAS, HER2, BRAF, MET, ALK, RET, ROS1, and FGFR. Driver-negative cases were further analyzed by a comprehensive RNA-based nextgeneration sequencing (NGS) fusion assay for novel fusions. Results: In total, we profiled 1681 lung adenocarcinomas, among which 255 cases were common driver-negative. One hundred seventy-seven cases had sufficient tissue for NGS fusions screening, which identified eight novel fusions. NRG1 fusions occurred in 0.36% of all lung adenocarcinoma cases (6 of 1681 cases), including 4 CD74-NRG1-positive cases, 1 RBPMS-NRG1-positive case, and 1 novel ITGB1-NRG1-positive case. Furthermore, another 2 novel fusions were also detected, including 1 EGFR-SHC1 fusion and 1 CD47-MET fusion, both of which were in-frame and retained the functional domain of the corresponding kinases. No fusion event was detected for NTRK, KRAS, BRAF or HER2 genes in this cohort. Detailed clinicopathologic data showed that invasive mucous adenocarcinoma (three of eight cases) and acinar-predominant adenocarcinoma (three of eight cases) were the most prevalent pathologic subtypes among novel fusions. Conclusions: Fusions affecting NRG1, EGFR, and MET were detected in 0.48% of unselected lung adenocarcinomas, and NRG1 fusions ranked the most prevalent fusions in common driver-negative lung adenocarcinomas from Chinese population. RNA-based NGS fusion assay was an optional method for screening actionable fusions in common driver-negative cases.

No abstract