Abstract 4815: Tumor heterogeneity of advanced primary lung cancer evaluated by multiregion sequencing

Abstract

Abstract Background: Cancers are composed of cells with distinct genetic and phenotypic characteristics. Tumor heterogeneity in each patient may influence on personalized medicine strategies that depend on results from single tumor-biopsy samples. However, tumor heterogeneity in advanced primary lung cancer has not been well studied. The purpose of this study was to investigate the tumor heterogeneity in advanced primary lung cancer. Methods: We sequenced fourteen regions from four patients who were suspicious for primary lung cancer with multiple lymph node metastasis. Tumor samples were obtained from primary tumor and metastatic lymph node(s) or distant metastasis using bronchoscopic forcep biopsy, endobronchial ultrasound-guided transbronchial needle aspiration, and percutaneous needle biopsy. The profiles of somatic mutations, copy number alterations and gene expression were compared among primary tumor and metastatic sites in each patient. Clonal evolution was evaluated using the concept of cancer cell fraction by SciClone analysis. Results: We performed multiregion whole exome sequencing and RNA sequencing on three non-small cell lung cancers (2 adenocarcinomas [TH1 and TH4] and 1 squamous cell carcinoma [TH2]) and one small cell lung cancer (TH3). EML4-ALK fusion was noticed in TH1 and TH4. There was profound tumor heterogeneity in terms of somatic mutation, copy number alteration, or gene expression in each patient. The frequency of private somatic mutation from spatially distinct regions were 59% in TH1, 44% in TH2, 13% in TH3, and 30% in TH4. Known driver mutation was also heterogeneous in TH1 and TH2. Analysis of the clonal architecture confirmed the presence of clonal heterogeneity in each patient. Phylogenetic reconstruction revealed the evidence of branched clonal evolution. Conclusions: Tumor heterogeneity was noticed from spatially distinct regions from advanced primary lung cancers. The single biopsy specimens may not represent the whole landscape of genetic alteration in advanced primary lung cancers. Citation Format: Sang-Won Um, Je-Gun Joung, Su Yeon Lee, Joon Seol Bae, Jinha Park, Woong-Yang Park. Tumor heterogeneity of advanced primary lung cancer evaluated by multiregion sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4815. doi:10.1158/1538-7445.AM2015-4815