Distinct genomic instability landscape of lung adenocarcinoma associated with treatment and metastasis.

Abstract

9534 Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC). Genomic instability, defined as genome-wide copy number alterations, is a key pathogenic signature which occurs at the early stage of most cancers and is associated with an increased risk of recurrence or death. We examined the pattern of genomic instability in primary and metastatic LUAD. Methods: We performed deep targeted sequencing (425 genes) of 3395 tissue samples and whole exome sequencing (WES) of 60 tissue samples from LUAD patients. Whole-genome doubling (WGD) and arm level aneuploidy were analyzed to uncover correlation with clinical phenotypes and other genomic alterations including driver mutations, tumor mutation burden (TMB), and microsatellite instability (MSI). Results: Overall, targeted sequencing revealed that WGD occurred in 64.33% LUAD samples, which was comparable with WES results. Compared to primary site, metastasis exhibited higher proportion of WGD (1.14 fold). Specifically, liver metastasis has the highest WGD percentage among metastasis sites (~87.5%; 1.40 fold increase compared to primary). Interestingly, patients who received tyrosine kinase inhibitors (TKI) had higher frequency of WGD than patients without TKI treatment. In addition, TMB was higher in WGD+ patients but MSI status was not significantly different between groups. Arm-level aneuploidy was prevalent in this cohort. The most common amplification events were 7p gain (62%), 5p gain (54%), and 8q gain (53%); top deletion events were 19p loss (47%), 15q loss (42%), and 10 q loss (41%). Patients with EGFR or TP53 mutation were more likely to have aneuploidy compared to wildtypes. Subgroup analysis showed distinct patterns of aneuploidy among metastasis sites, suggesting organ-specific alterations. Evolution analysis showed 7p gain was an early event common in primary tumor whereas metastatic tumor had multiple distinct evolutionary trajectories following 7p gain. Several copy number signatures were associated with specific TKI and chemotherapies. For example, TKI-naïve tumors lacked 7p gain but had 19p loss as the most common alteration. Conclusions: The genomic landscape of LUAD was characterized by widespread large-scale copy number alterations including WGD and chromosomal aneuploidy. Metastasis had elevated level of aneuploidy compared to primary tumors which were specific to metastatic site. Copy number signature associated with different treatments may contribute to distinct long-term survival and side effects among patients.