View Abstract

A7091 - Genomic Underpinnings of Tumor Behavior in Early Lung Adenocarcinoma
Author Block: J. Qian1, S. Zhao2, Y. Zou1, S. Rahman1, T. Stricker3, H. Chen2, C. A. Powell4, A. C. Borczuk5, P. P. Massion6; 1Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, United States, 2Departments of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States, 3Departments of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States, 4Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States, 5Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, United States, 6Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, United States.
RATIONALE: Our understanding of the biological underpinnings of the progression of the early stage of lung adenocarcinoma (ADC) remains limited. We hypothesized that the behavior of early adenocarcinoma can be predicted based on genomic underpinnings. METHODS: In this study, we collected 21 adenocarcinoma in situ (AIS), 27 minimally invasive adenocarcinoma (MIA) and 54 fully invasive adenocarcinoma genomic DNA. The tumor DNA samples were subjected to a deep next generation sequencing (NGS) targeting a custom 341 cancer gene panel. RESULTS: In total, we identified 329 somatic mutations of 163 genes in AIS, 505 mutations of 194 genes in MIA, 1160 mutations of 288 genes in ADC. The mutation burden was significantly greater in ADC after adjusting for age and predicted smoking status. Overall, increased mutational intratumor heterogeneity was displayed from AIS, MIA to ADC, indicating phenotypic evolution. In addition to EGFR, we found 12 most common mutated genes shared in three groups, including three epigenetic modifiers (KMT2B,KMT2C and KMT2D), two critical players in cell cycle control and maintenance of genomic stability (APC and ATM), two NOTCH gene member (NOTCH2 and NOTCH3), CRIPAK, EPPK1,PRKDC and PALLD. Progressively increased mutation numbers of eleven genes including KRAS, TP53 and KMT2D were observed from AIS, MIA to ADC. We speculate these genes are under selective advantage during lung adenocarcinoma development and progression, which was further demonstrated in ensemble-level progression models using phylogenetic analysis. Our data suggested CRIPAK and EPPK1 as two novel early driver genes mutually exclusively mutated in 23% of AIS/MIA or 26% of ADC lacking mutations for TP53, EGFR and KRAS. Finally, ALK and NOTCH2 mutations were found to be significantly associated with overall poor survival. CONCLUSIONS: Using a targeted sequencing we demonstrated a sequence of driver events and clonal diversity in the progression of early lung adenocarcinoma. Our work has implications in the management of early adenocarcinoma of the lung including selection of individuals for adjuvant therapy.