Comprehensive molecular and immune profiling of non-small cell lung cancer and matched distant metastases to suggest distinct molecular mechanisms underlying metastasis.

Abstract

8541 Background: Despite complete resection, many non-small cell lung cancer (NSCLC) patients still develop and succumb to distant metastases. Previous studies suggested distant metastasis may be due to genomic evolution and/or suppressed immune surveillance. However, the relationship between specific genomic alterations and immune surveillance has not been systemically studied. Methods: We performed whole exome sequencing, RNA-Seq, methylation microarray, immunohistochemistry using multiple immune markers, and T cell receptor sequencing on 7 pairs of NSCLC primary tumors and matched metastases including 6 metachronous brain and 1 synchronous liver metastases. Results: On average, 84% of all somatic mutations (54% to 97%) and all 28 canonical cancer gene mutations were shared between primary tumors and paired distant metastases. Metastases also resembled paired primary tumors closely in regard to somatic copy number aberration profiles, methylation profiles. Subclonal analysis showed almost identical clonal architectures in 4 of 7 pairs of primary tumor and metastasis comparable to the similarity observed between different regions within the same tumors. The other 3 pairs, however, displayed clear evidence of clonal evolution. We validated these findings in a published dataset consisting of 38 pairs of primary NSCLC tumors and matched distant metastases. The RNA-Seq data showed that 25 of the top 35 significantly down-regulated signaling pathways in metastases relative to primary tumors were related to immune activation, which was validated in an independent cohort of 41 primary NSCLC tumors and distant metastases using NanoString’s PanCancer Immune Profiling Panel. Conclusions: Our data suggest that molecular mechanisms underlying postsurgical distant metastasis may be variable among NSCLC patients. While genomic evolution may play a role in development of metastasis in some patients, distant metastasis may be early event during carcinogenesis without further genomic evolution in a substantial proportion of NSCLC patients. Furthermore, immune suppression may be a characteristic of cancer cells of metastatic capacity.