Abstract 40P
Background
Progression and metastasis of early-to-mid stage lung cancers exhibited great diversity and have not been systemically studied to date. Evolutionary genomics underlying lung cancer progression and metastasis may provide guidance for patient stratification and personalized disease management.
Methods
We collected 160 primary tumors (PTs, 474 regions) and 112 lymph node metastases (LNMs) from 125 patients with stage I-III resectable lung cancer and performed targeted sequencing. We reconstructed the sample phylogeny of each patient and investigated evolutionary subtypes of PTs and metastatic trajectories of LNMs at the clonal resolution.
Results
In progressive clonal evolution of PTs, intratumor heterogeneity decreased with tumor growth while clonal diversity increased with tumor differentiation. NF1 and RB1 mutations were selected during clonal sweep. We categorized lung adenocarcinomas into 7 evolutionary subtypes and elaborated their correlation with clinicopathological features. Subtypes with late-acquired TP53 mutations indicated worse DFS than those initiated by TP53 mutations (HR = 7.98; P = 0.0070). We further identified NF1 and TP53 mutations as potent metastatic drivers and unfavored prognostic markers for metastasis-free patients (P = 0.021 and 0.0017, respectively). An overall trend of sequential metastatic spreading was observed, on the basis of which we engraved fine classifications of seeding modes by clonality and trajectories. The majority of LNMs (67.9%) were seeded multiclonally, among which three cases showed profound evidence for LN-mediated metastasis. Moreover, multiple metastases of distinct evolutionary origins indicated higher risk of relapse than those of common origins.
Conclusions
Our results depict the evolutionary patterns of PTs and LNMs in patients with resectable lung cancers. Features such as evolutionary subtypes of PTs and phylogenetic origins of LNMs may serve as prognostic markers for optimal treatment in lung cancer patients. Our study highlights the clinical significance of evolutionary genomics in the understanding of tumor progression and disease management.
Clinical trial identification
ChiCTR1900022521.
Editorial acknowledgement
Legal entity responsible for the study
Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research.
Funding
Key Project of Cutting-edge Clinical Technology of Jiangsu Province (BE2016797); National Science Foundation of China (81872378, 81672295, 81572261, 81501977); The Project of Jiangsu Provincial Medical Talent (ZDRCA2016033).
Disclosure
X. Fan, M. Wu, H. Bao, R. Yu, X. Wu, Y. Shao: Financial Interests, Personal, Full or part-time Employment: Nanjing Geneseeq Technology Inc. All other authors have declared no conflicts of interest.