Abstract 2982: Genome sequencing reveals the multicentric nature of multiple synchronous lung adenocarcinomas
Authors: Zhang Jianjun , Liu Yu , Li Lin , Zhang Jianhua , Yin Guangliang , Lin Dongmei , Liu Xiangyang , Cheung Hannah , Seth Sahil , Song Xingzhi , Mao Xizeng , Zhang Jiexin , Cheng Shujun , Futreal Andrew , Gao Yanning 
Published: August 2015

Abstract
Background: Genomic heterogeneity of lung cancers from different patients has been well documented, reflecting distinct genetic background and different carcinogen exposures. On the other hand, our recent study has demonstrated limited heterogeneity between different regions within the same tumor (Zhang, et al. Science, 2014: 346:256-9). Multiple synchronous lung cancer (MSLC) is a unique set of lung cancers with multiple tumors arising in the context of identical constitutional genetic background and shared carcinogen exposures. MSLC presents a clinical dilemma as to whether they are intrapulmonary metastasis or true multicentric primary tumors. Methods: We applied whole-genome/exome sequencing to 15 tumors plus one metastatic regional lymph node from six patients with multiple synchronous lung adenocarcinomas. All nonsynonymous mutations were subjected to mass spectrometry or Sanger sequencing for validation. Results: A total of 876 nonsynonymous mutations were detected and validated. With the exception of a metastatic lymph node that shared 52 mutations with the primary tumor suspected as its origin by clinicopathological assessment, all tumors, including one highly suspicious for intrapulmonary metastasis, showed distinct genomic profiles, indicating that all MSLC in this study are consistent with true multicentric primary lung adenocarcinomas. When compared to TCGA study, these synchronous multifocal tumors are no more similar than similarly staged lung adenocarcinomas from unrelated patients. Although similar mutational spectra were observed between different tumors from some patients, at least three patients showed significantly different mutational spectra in different tumors indicating multiple mutational processes in play during the development of individual, independent tumors within the same lung subjected to common exposures on the same constitutional genetic background. Interestingly, the same known cancer genes including EGFR, KRAS and STK11/LKB1 demonstrated distinct mutational patterns in different tumors from the same patients suggesting that even on the identical genetic background and common exposures, development of multicentric lung adenocarcinomas can be driven by distinct molecular events in different tumors, but there may be constraint around certain genes/pathways critical for carcinogenesis in specific patients. Conclusions: The dramatic genomic heterogeneity in multiple synchronous lung adenocarcinomas within the same patients with identical constitutional genetic background and environmental exposures indicates the complexity of lung adenocarcinoma carcinogenesis. These data suggest that detailed molecular profiling up to genome-scale analyses of all lesions may be necessary for MSLC to distinguishing multiple primary lung cancers from true intrapulmonary metastasis and accurately exploit biomarker-driven management.
Citation Format: Jianjun Zhang, Yu Liu, Lin Li, Jianhua Zhang, Guangliang Yin, Dongmei Lin, Xiangyang Liu, Hannah Cheung, Sahil Seth, Xingzhi Song, Xizeng Mao, Jiexin Zhang, Shujun Cheng, Andrew Futreal, Yanning Gao. Genome sequencing reveals the multicentric nature of multiple synchronous lung adenocarcinomas. [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 2982. doi:10.1158/1538-7445.AM2015-2982