Abstract 156: Integrated exome and transcriptome sequencing of primary lung cancers and paired distant metastases

Abstract

Abstract Background: The precise molecular mechanisms underlying metastasis of nonsmall cell lung cancers (NSCLC) are largely unknown. Two recent studies comparing genomic landscapes of primary NSCLC tumors and paired brain metastases suggested branched evolution, where all metastatic and primary tumors shared a common ancestor yet continued to evolve independently. The integrated genomic and transcriptomic profiles of primary NSCLC and metastases have not been studied in any details. Methods: We performed whole exome sequencing (WES) and RNA sequencing (RNA-seq) of surgically resected primary tumors and paired distant metastases from 7 patients with NSCLC. Results: Totally, 6,945 somatic mutations, including 1,702 non-silent (stop-gain, stop-loss, frameshift, splicing site and nonsynonymous) mutations were identified by WES. Metastases trended to have larger mutation burdens compared to paired primary tumors, although the difference was not statistically different (average 595 mutations per tumor in primary tumors versus 852 mutations per tumor in metastases, respectively, p = 0.54). On average, 51% of all mutations (24% to 93%) were shared between primary tumors and metastases. We identified 14 canonical cancer gene mutations in this cohort of patients, defined as mutations that lead to amino acid changes identical to those found previously in cancer genes or disrupting mutations in tumor suppressor genes, all of which were shared between primary tumors and paired distant metastases. In addition, metastases resembled paired primary NSCLC tumors closely in regard to somatic copy number aberration profiles and mutation signatures. Pathway analysis from RNA-seq data demonstrated that 25 of the 35 signal transduction pathways that were significantly down regulated in metastases relative to primary NSCLC tumors were related to immune activation. Validation study with a larger patient cohort is in progress. Conclusions: Although branched evolution is a common phenomenon during metastasis of NSCLC, majority of canonical cancer gene mutations are probably early molecular events likely acquired before metastasis initiates. Mutation mechanism may be determined early during carcinogenesis and preserved during cancer evolution even at the metastatic sites. Immune suppression may be one characteristic feature of cancer cells of metastatic capacity. Citation Format: Jianjun Zhang, Chia-Chin Wu, Jianhua Zhang, Junya Fujimoto, Xingzhi Song, Xizeng Mao, Huadong Sun, Sahil Seth, Rebecca Thornton, Marcus Coyle, Latasha Little, Curtis Gumbs, Carmen Behrens, Chi-Wan Chow, Erik Sulman, Ganesh Rao, Stephen Swisher, Ignacio Wistuba, John Heymach, Andrew Futreal, Daniel Gomez. Integrated exome and transcriptome sequencing of primary lung cancers and paired distant metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 156.