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Evolutionary trajectories and clonal migration underlying tumor progression and lymph node metastasis in resectable lung cancer

ABSTRACT: In this prospective study, targeted deep sequencing was performed on a total of 160 primary tumors (474 regions) and 112 lymph nodes from 125 patients with stage I-III lung cancer (LuCaTH). Progressive evolution at clonal divergence scale was observed while specific driver events were positively selected for clonal sweeps during tumor development. Between-region genetic divergence (BRGD) of tumors were assessed and positively correlated with tumor differentiation. A machine learning algorithm was employed to evaluate clinicopathological and molecular parameters of primary tumors underlying lymph node metastasis. By analyzing clonal lineages and metastatic trajectories across multiple nodal stations, we unraveled a common sequential LNM seeding pattern but with divergent modes of clonal spread.

PROVIDER: EGAS00001005242 | EGA |

REPOSITORIES: EGA

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Project description:Background: While much progress has been accomplished in the understanding of radiation-induced immune effects in tumors, little is known regarding the mechanisms involved at the tumor draining lymph node (TDLN) level following tumor irradiation. The objective of this retrospective study was to assess the immune and biological changes arising in TDLN upon concurrent chemoradiotherapy of primary non-small cell lung cancer (NSCLC) tumors. Methods: Patients with proved localized (cN0M0) NSCLC, treated by radical surgery plus lymph node dissection with (CRT+) or without (CRT-) neoadjuvant chemoradiotherapy, whereby radiotherapy was targeted on the primary tumor with no significant incidental irradiation of the TDLN station (stations XI or X), were identified. Bulk RNA-Seq of TDLNs was performed and data were analyzed based on differential gene expression (DEG) and gene sets enrichment. Results: Sixteen patients were included and 25 TDLNs were analyzed: 6 patients in the CRT+ group (12 samples) and 10 patients in the CRT- group (13 samples). Overall, 1001 genes were differentially expressed between the two groups (CRT+ and CRT-). Analysis with g-profiler revealed that gene sets associated with antitumor immune response, inflammatory response, hypoxia, angiogenesis, epithelial mesenchymal transition and extra-cellular matrix remodeling were enriched in the CRT+ group, whereas only gene sets associated with B cells and B-cell receptor signaling were enriched in the CRT- group. Unsupervised dimensionality reduction identified two clusters of TDLNs from CRT+ patients, of which one cluster (cluster 1) exhibited higher expression of pathways identified as enriched in the overall CRT+ group in comparison to the CRT- group. In CRT+ cluster 1, 3 out of 3 patients had pathological complete response (pCR) or major complete response (MPR) to neoadjuvant CRT, whereas only 1 out of 3 patients in the other CRT+ cluster (cluster 2) experienced MPR and none exhibited pCR. Finally, pathway comparison to published data from pre-metastatic TDLNs uncovered similarities with CRT+ cluster 1. Conclusion: Neoadjuvant concurrent chemoradiotherapy of the primary tumor in N0 NSCLC patients is associated with distinct microenvironment and immunological patterns in TDLNs as compared to TDLNs from patients with non-irradiated tumors. Our data are in line with studies showing superiority of lymph node sparing irradiation of the primary tumor in the induction of systemic antitumor immunity.

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Evolutionary trajectories and clonal migration underlying tumor progression and lymph node metastasis in resectable lung cancer

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