Abstract 3530: Gene expression alterations associated with histologic aggressiveness in stage I lung adenocarcinomas
Authors: Zhang Jiarui , Burks Eric , Beane Jennifer , Sullivan Travis , Liu Gang , Dubinett Steven , Lenburg Marc , Spira Avrum 
Published: August 2019

Abstract
RATIONALE:
The National Lung Screening and Nelson Trials demonstrated a 20% and 26% (for men) reduction, respectively in lung cancer mortality for patients screened using low-dose CT. However, lung cancer screening has the potential for over-diagnosis of indolent tumors. Therefore, we sought to identify molecular features that could distinguish indolent from aggressive early stage lung tumors based on histologic aggressiveness profiling, with the ultimate goal being to translate these findings into biomarkers that could inform post-biopsy/surgery management.
METHODS:
63 FFPE samples of stage I lung adenocarcinomas were included for pathologic annotation and Whole Exome sequencing. An average of 48.2±15.6 million total reads per sample were generated with 78.4%±4.8% reads uniquely mapped. Tumors were categorized into 3 groups based on histologic features previously associated with tumor aggressiveness: Minimally-Aggressive (n=18): containing zero aggressive components (e.g. zero solid/cribriform); Medium-Aggressive (n=19): not yet dominated by aggressive components; Highly-Aggressive (n=26): solid/cribriform predominant. Tumor histology was characterized for percentage of lepidic, acinar, papillary, micro-papillary, solid and cribriform components. Negative binomial models were used to identify genes whose expression was associated with tumor histology. Estimate Algorithm was used to estimate immune cell type infiltration of these tumors.
RESULTS:
430 genes (FDR q&lt;0.05) were differentially expressed between the three histologic groups. Genes with elevated expression in the Medium- and Highly-Aggressive subgroups were enriched for genes with roles in cell-cycle regulation and the EMT transition. The genes elevated in the Minimally-Aggressive subgroup were enriched for genes with roles in inflammatory pathways and cytokine production. This gene signature was also associated with tumor invasiveness and mitotic grades (p&lt;0.05). Using the Estimate Algorithm, we compared whether the three histologic groups had differential immune cell infiltrations using hallmark gene sets of lymphocytes and myeloid cells. We identified that Minimally-Aggressive subgroups had significantly higher Th-1, Tfh, Th17 and NK cell infiltration than Medium- and Highly-Aggressive subgroups (adjusted p value&lt;0.05).
CONCLUSION:
We identified gene expression alterations among stage I adenocarcinomas associated with histologic features of tumor aggressiveness. This gene signature may help identify more indolent tumors and potentially impact their post biopsy/surgery clinical management.
Citation Format: Jiarui Zhang, Eric Burks, Jennifer Beane, Travis Sullivan, Gang Liu, Steven Dubinett, Marc Lenburg, Avrum Spira. Gene expression alterations associated with histologic aggressiveness in stage I lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3530.