Genomic Underpinnings of Tumor Behavior in In Situ and Early Lung Adenocarcinoma
- 15 March 2020
- journal article
- research article
- Published by American Thoracic Society in American Journal of Respiratory and Critical Care Medicine
- Vol. 201 (6), 697-706
- https://doi.org/10.1164/rccm.201902-0294OC
Abstract
Rationale: We have a limited understanding of the molecular underpinnings of early adenocarcinoma (ADC) progression. We hypothesized that the behavior of early ADC can be predicted based on genomic determinants. Objectives: To identify genomic alterations associated with resected indolent and aggressive early lung ADCs. Methods: DNA was extracted from 21 ADCs in situ (AISs), 27 minimally invasive ADCs (MIAs), and 54 fully invasive ADCs. This DNA was subjected to deep next-generation sequencing and tested against a custom panel of 347 cancer genes. Measurements and Main Results: Sequencing data was analyzed for associations among tumor mutation burden, frequency of mutations or copy number alterations, mutation signatures, intratumor heterogeneity, pathway alterations, histology, and overall survival. We found that deleterious mutation burden was significantly greater in invasive ADC, whereas more copy number loss was observed in AIS and MIA. Intratumor heterogeneity establishes early, as in AIS. Twenty-one significantly mutated genes were shared among the groups. Mutation signature profiling did not vary significantly, although the APOBEC signature was associated with ADC and poor survival. Subclonal KRAS mutations and a gene signature consisting of PIK3CG, ATM, EPPKI, EP300, or KMT2C mutations were also associated with poor survival. Mutations of KRAS, TP53, and NF1 were found to increase in frequency from AIS and MIA to ADC. A cancer progression model revealed selective early and late drivers. Conclusions: Our results reveal several genetic driver events, clonality, and mutational signatures associated with poor outcome in early lung ADC, with potential future implications for the detection and management of ADC.Keywords
This publication has 54 references indexed in Scilit:
- Effects of Co-occurring Genomic Alterations on Outcomes in Patients withKRAS-Mutant Non–Small Cell Lung CancerClinical Cancer Research, 2018
- Clinically significant sub-clonality for common drivers can be detected in 26% of KRAS/EGFR mutated lung adenocarcinomasOncotarget, 2017
- KEGG: new perspectives on genomes, pathways, diseases and drugsNucleic Acids Research, 2016
- Algorithmic methods to infer the evolutionary trajectories in cancer progressionProceedings of the National Academy of Sciences of the United States of America, 2016
- CAPRI: efficient inference of cancer progression models from cross-sectional dataBioinformatics, 2015
- APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myelomaNature Communications, 2015
- Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome AtlasPLoS Medicine, 2015
- SciClone: Inferring Clonal Architecture and Tracking the Spatial and Temporal Patterns of Tumor EvolutionPLoS Computational Biology, 2014
- Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway.2002
- Molecular portraits of human breast tumoursNature, 2000