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Intra-tumor heterogeneity of localized lung adenocarcinomas defined by multi-region sequencing

Background: Intra-tumor heterogeneity (ITH) may have profound impacts on biopsy strategy, characterization of actionable targets, treatment planning, and drug resistance. ITH of lung cancers has not been well studied. Methods: We performed multi-region whole exome sequencing (average sequencing depth 277x) on 48 tumor regions from 11 resected lung adenocarcinomas (8 stage I, 2 stage II and one stage III tumors) followed by deep sequencing validation (average sequencing depth 863x). Results: All tumors showed clear evidence of spatial ITH. On average, 76% of all mutations and 20/21 known cancer gene mutations were present in all regions of individual tumors (trunk mutations). Copy number analysis did not show substantial difference in large-scale chromosome aberrations. A canonical KRAS p.G12C mutation was detected in only 1 of 4 tumor regions (branch mutations) at exome depth but detected in all four tumor regions (trunk mutations) at increased sequencing depth. In addition, many heterogeneous branch mutations defined by exome sequencing were detectable in all regions of individual tumors with increasing sequencing depth. Significant differences in mutational spectrum were observed in 6 tumors indicating that specific mutational processes were likely operative at different times during development of these tumors. With a median follow up of 21 months post surgery, 3 patients have relapsed and all 3 patients presented with significantly larger fractions of subclonal mutations in their primary tumors. Conclusions: Although multi-region sampling is still required to fully assess ITH complexity, single biopsy analysis at appropriate depth might be sufficient to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. Larger subclonal mutation fractions may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas. Studies on larger cohort, ideally with comprehensive clinical annotation and repeat biopsy at relapse are needed to fully understand the clinical impact of ITH.

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Dataset ID Description Technology Samples
EGAD00001000984 Illumina HiSeq 2000 59
EGAD00001000985 Illumina HiSeq 2000 58
Publications Citations
Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing.
Science 346: 2014 256-259
Between-region genetic divergence reflects the mode and tempo of tumor evolution.
Nat Genet 49: 2017 1015-1024
TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence.
Cancer Discov 7: 2017 1088-1097
Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing.
Nat Commun 9: 2018 216
Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy.
Nat Commun 10: 2019 657