Abstract 3782: Tracking the evolution of nasopharyngeal carcinoma metastasis
Authors: Ming Yuan Chen, Zhi-Xiang Zuo, Rui You, Xiao-Long Zhang, Mei Lin
Journal: Cancer Research (2019)

Abstract Understanding the evolutionary history of distant metastasis in Nasopharyngeal carcinoma (NPC) is important for curing NPC and has not been systematically investigated to date. Here, we profiled whole exomes/genomes of 142 bulk samples, and transcriptomes of 60 bulk samples from 42 NPC patients with matched primary tumor, and regional lymph node/distant metastasis tumor tissues. Among them, 55755 single cells from 2 patients was also sequenced. In addition, we analyzed radiomic data from 600 NPC patients. We observed that NPC primary, regional lymph node metastasis and distant metastasis tumors had concordant mutation profiling and intratumor heterogeneity. Furthermore, we found the genetic events selected during metastasis were enriched in pathways related to metastasis, such angiogenesis, Notch and Wnt signaling. Some critical genetic events were identified, such as mutations in FAT1, RPLP1, TET2, NFKBIA, NOTCH1/3 and ARID1A, copy number variations in NOTCH2 and ARID1A. According to the mutation based phylogenetic tree and single cell RNA-Seq data, two distinct dissemination routes of distant metastases were observed, including lymphatic dissemination from regional lymph node metastases and hematogenous dissemination from primary tumors. We observed that the two different metastatic dissemination routes had different genetic mechanisms revealed by profound genomic and transcriptomic evidence. The hematogenous and lymphatic route had distinct mutation signatures, where hematogenous route was significantly enriched with higher DNA mismatch repair related mutation signature compared to lymphatic route. The bulk and single cell RNA-Seq data showed that the lymphatic route had higher activity of Epithelial-mesenchymal transition (EMT) signaling, while the hematogenous route was characterized by higher expression of INF-γ response genes and higher fraction of exhausted CD8+ T cells. Moreover, the two dissemination routes exhibited evidently different clinical outcomes. The radio image data showed that the hematogenous and lymphatic routes significantly differed in the size of primary lesion, and the range of involved lymph nodes. The radiomic data further indicated that the hematogenous and lymphatic routes could be clearly separated according to radiomic features. By applying the radiomic model to a larger cohort, we found hematogenous route had poorer survival outcome compared to lymphatic route. Finally, at cellular resolution, we observed the primary tumor cells could be separated into two distinct clones, including non-metastatic clone and metastatic-like clone. The metastatic-like clone was characterized by a significant reduction of a ribosomol protein, RPL22. We experimentally confirmed that the reduction of RPL22 could activate NFKB pathway, thereby promoting NPC cell metastasis. Citation Format: Ming Yuan Chen, Zhi-Xiang Zuo, Rui You, Xiao-Long Zhang, Mei Lin. Tracking the evolution of nasopharyngeal carcinoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3782.