Abstract 2210: Chromosome arm aneuploidy landscape in lung adenocarcinoma
Authors: Bao Hua , Han Ming , Shen Yi , Wu Xue , Shao Yang 
Published: July 2021

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. Overall aneuploidy frequency in LUAD have been previously documented. We aimed to assess whether specific chromosome arm aneuploidy (CAA) patterns can be found in primary tumor and different metastatic sites, and across patients with different driver mutations. We also investigated CAA and driver mutation co-occurrence patterns in LUAD, as well as probable order of CAA acquisition.

Methods: We performed targeted panel sequencing (425 cancer-related genes) on 3533 tissue samples from LUAD patients. CAA status (arm gain or loss) was derived from segmental copy number analysis using Sequenza, accounting for purity and ploidy. 4 types of CAA analysis were conducted: total CAA burden, gain-loss pattern, co-occurrence/exclusivity, and population level CAA progression assessed by Tronco on network-based stratified (NBS) subtypes.

Results: Use of panel sequencing data for analysis of CAA status was validated against WES results, and achieved high concordance (Kappa: 0.75, Pearson: 0.85). Primary tumor and different metastatic sites had dramatic differences in CAA burdens (p=3.4e-06). Liver and brain had more arm losses than gains compared to primary (q=0.047 and 0.049 respectively). Different driver mutation groups also had significant difference in CAA burden (p&lt;2.2e-16). BRAF group had more arm gains than losses; whereas PIK3CA had more arm losses than gains. TP53 mutation status had a moderating effect on both CAA burden and gain-loss pattern across metastatic sites and driver mutation groups. EGFR 19del and L858R mutations showed significant differences in CAA co-occurrence/exclusion. EGFR 19del tend to co-occur with 4q-, 5p-, 5q-, 8q+, 9p+, 16q+, 17p+, 17q-, 22q-, and was in exclusion with 14q-. EGFR L858R co-occurred with 4q+, but was in exclusion with 1p-, 8p+ and 16p-. MET significantly co-occurred with 1q-, and PIK3CA with 2p+. Clustering of LUAD patients using NBS gave us 2 tight clusters with high silhouette score (0.86). These two LUAD subtypes showed distinct orders of CAA acquisition. Both clustered subtypes began with acquisition of 7p gain. Subtype 1 is dominated by initial arm gains, followed by few arm losses, seen in previously published literature; whereas subtype 2 began with a simultaneous acquisition of 19p loss, with further additions of many arm losses, before eventual accumulation of arm gains. Proportion of these 2 subtypes varied across primary and metastatic sites, and driver mutant groups.

Conclusions: There are significant differences in arm aneuploidy patterns across metastatic sites and mutation groups. Overall, LUAD patients exhibit a unique pattern of co-occurrence and exclusivity between CAA and driver mutations, as well as two subtypes with distinct CAA evolution trajectories. These CAA patterns may hold biological meaning and may be useful predictors of clinical outcomes and warrants further investigation.

Citation Format: Hua Bao, Ming Han, Yi Shen, Xue Wu, Yang Shao. Chromosome arm aneuploidy landscape in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2210.