Multiregion Sequencing Identifies Intratumor Heterogeneity in NSCLC

Targeting of oncogenic drivers in non–small cell lung cancer (NSCLC) represents an attractive therapeutic strategy; however, early genomic characterization of these tumors suggests that intratumor heterogeneity may present a challenge to effective treatment. Zhang and colleagues assessed the extent of genomic diversity in NSCLC by performing whole-exome sequencing on 48 regions from 11 lung adenocarcinomas, primarily consisting of stage I disease. Although the majority of mutations were detected in all tumor regions, evidence for intratumor heterogeneity was also observed in each tumor. Phylogenetic analysis revealed that mutations in cancer driver genes and copy-number alterations of known cancer genes occurred early in tumor development. Importantly, patients who experienced tumor relapse displayed an increased proportion of subclonal mutations in primary tumors, suggesting that subclonal mutations may represent a biomarker and driver of tumor recurrence. Consistent with these findings, de Bruin and colleagues detected significant intratumor heterogeneity and evidence of branched tumor evolution in NSCLC using whole-exome and/or whole-genome sequencing of 25 spatially distinct regions from seven stage IB–IIIB tumors. Importantly, however, in addition to clonal driver mutations occurring early in tumor evolution, this analysis also identified the presence of subclonal cancer driver mutations and late-stage copy-number alterations, challenging the notion that a single biopsy is sufficient to define all tractable oncogenic events. In addition, temporal analysis of genomic instability in tumors from former smokers suggested a prolonged latency period between genome-doubling and detection of clinical disease. Furthermore, analysis of point mutations by both groups revealed a global shift in the mutational landscape and diversity in genomic instability processes over time, with a decrease in smoking-associated mutations in late tumors and an increase in subclonal C>T and C>G mutations associated with APOBEC cytidine deaminase activity. Together, these results emphasize that deep sequencing efforts of multiple tumor regions will likely be required to accurately assess intratumor heterogeneity, identify subclonal oncogenic drivers, and predict patient relapse in NSCLC.

Zhang J, Fujimoto J, Zhang J, Wedge DC, Song X, Zhang J, et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 2014;346:256–9.

de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 2014;346:251–6.

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