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Lung adenocarcinoma (LUAD) is a heterogeneous disease. Our study aimed to understand the unique molecular features of preinvasive to invasive LUAD subtypes. We retrospectively analyzed the clinical, histopathological, and molecular data of 3,254 Chinese patients with preinvasive lesions (n = 252), minimally invasive adenocarcinomas (n = 479), and invasive LUAD (n = 2,523). Molecular data were elucidated using a targeted 68-gene next-generation sequencing panel. Our findings revealed four preinvasive lesion-predominant gene mutations, including MAP2K1 insertion-deletions (indels), BRAF non-V600E kinase mutations, and exon 20 insertions (20ins) in both EGFR and ERBB2, which we referred to as mutations enriched in AIS (MEA). The detection rate of MEA in invasive tumors was relatively lower. MAP2K1 missense mutations, which were likely passenger mutations, co-occurred with oncogenic driver mutations, while small indels were mutually exclusive from other genes regardless of the invasion level. BRAF non-V600E kinase-mutant invasive adenocarcinomas (IAC) had significantly higher mutation rates in tumor suppressor genes but lower frequency of co-occurring oncogenic driver mutations than non-kinase-mutant IAC, suggesting the potential oncogenic activity of BRAF non-V600E kinase mutations albeit weaker than BRAF V600E. Moreover, similar to the extremely low frequency of MAP2K1 indels in IAC, BRAF non-V600E kinase domain mutations co-occurring with TSC1 mutations were exclusively found in preinvasive lesions. Compared with EGFR L858R and exon 19 deletion, patients with preinvasive lesions harboring 20ins in either EGFR or ERBB2 were significantly younger, while those with IAC had similar age. Furthermore, our study demonstrated distinct mutational features for subtypes of oncogene mutations favored by different invasion patterns in adenocarcinomas. In conclusion, our data demonstrate distinct mutational features between preinvasive lesions and invasive tumors with MEA, suggesting the involvement of MEA in the early stages of tumorigenesis. Further pre-clinical studies are required to establish the role of these genes in the malignant transformation of LUAD.

Introduction It has been well established that EGFR Thr790Met is one of the major resistance mechanisms to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). Nevertheless, whether EGFR Thr790Leu (T790L), which shares the mutation site of Thr790 with EGFR Thr790Met, mediates resistance to EGFR TKIs remains elusive. The treatment options for patients harboring this rare mutation have not been reported. Methods Capture-based targeted ultradeep sequencing was performed on tumor and plasma samples collected at various treatment milestones from three patients with advanced lung adenocarcinoma undergoing targeted therapy. Results Needle biopsy of lymph node metastasis from patient 1 revealed EGFR T790L at disease progression on first-line treatment of gefitinib. Patient 2 had EGFR T790L identified from needle biopsy of lung tissue at disease progression on icotinib treatment. This patient was subsequently treated with osimertinib and achieved stable disease with a progression-free survival of 9 months. For patient 3, at disease recurrence after surgery, resected lung tumor tissue was retrieved for molecular profiling and revealed EGFR exon 19 deletion and EGFR T790L. The patient subsequently received osimertinib treatment and continued to benefit for 16 months and counting. She has maintained stable disease at the time of submission of this manuscript. Conclusions We revealed for the first time that EGFR T790L may serve as a potential resistance mechanism to first-generation EGFR TKIs. We also report the first clinical evidence of efficacy generated by osimertinib in patients with lung adenocarcinoma harboring primary or acquired EGFR T790L, shedding light on treatment options for this subset of patients.