Abstract 2741: Comprehensive molecular profiling of primary tumors and paired distant metastases in non-small cell lung cancer

Abstract

Abstract Despite complete resection, many non-small cell lung cancer (NSCLC) patients still develop and succumb to distant metastases, which is a major cause of cancer-related death worldwide. However, our understanding of the molecular mechanisms driving metastasis is rudimentary. We performed whole exome sequencing, RNA sequencing (RNA-seq), methylation microarray, and immunohistochemistry using multiple immune markers on 8 pairs of NSCLC primary tumors and matched distant metastases including 7 metachronous brain and 1 synchronous liver metastases. On average, 60% of all somatic mutations (22% to 90%) and 86% of canonical cancer gene mutations were shared between primary tumors and paired distant metastases. Metastases also resembled paired primary tumors closely in regard to their mutational spectrum, copy number aberrations, allelic imbalance, and methylation profiles. Genomic aberrations unique to metastases were rather patient-specific than commonly observed across multiple patients. Of particular interest, subclonal architecture analysis suggested that monoclonal metastatic seeding is a prevalent mode of metastasis in NSCLC. We validated these findings in a large published dataset consisting of 38 pairs of primary lung tumors and matched distant metastases. RNA-seq showed gene expression profiles in metastases were similar to those of paired primary tumors. Metastases commonly up-regulated metabolism-associated pathways and down-regulated immune-related pathways, consistent with the immunohistochemical staining data for CD3, CD4, CD8, CD20, CD68, PD1, and PD-L1. Our data suggest that distant metastasis is a late event during carcinogenesis and that a majority of genomic and epigenetic aberrations occur before metastatic outgrowth. While molecular mechanisms underlying postsurgical distant metastasis seem to be variable among NSCLC patients, immune suppression may be a common characteristic of cancer cells with metastatic plasticity. Citation Format: Won-Chul Lee, Daniel Gomez, Jianhua Zhang, Alexandre Reuben, Ali Jalali, Whijae Roh, Chia Chin Wu, Wei Lu, Chi-Wan Chow, Junya Fujimoto, Mara Antonoff, Cesar Moran, Erik Sulman, Ganesh Rao, Stephen Swisher, John Heymach, Ignacio I. Wistuba, Andrew Futreal, Jianjun Zhang. Comprehensive molecular profiling of primary tumors and paired distant metastases in non-small cell lung cancer [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 2741.