Abstract 112: Multi-omics analysis of molecular landscape and heterogeneity in fetal adenocarcinoma of the lung

Background: Fetal adenocarcinoma of the lung (FLAC) is a rare form of lung adenocarcinoma and was divided into high-grade (H-FLAC) and low-grade (L-FLAC) subtypes. Until now, much of the knowledge regarding FLAC is from case reports or small case series and there was no comprehensive multi-omics study of FLAC. Methods: A total of 20 FLAC patients who underwent tumor resection were retrospectively recruited in this study. Three regions from each of the 20 tumor specimens and matched normal tissue specimens were collected. Whole-exome sequencing, targeted bisulfite sequencing and whole transcriptome sequencing were performed on multi-regional tumor samples and normal tissue samples. Results: We compared our FLAC cohort with a conventional East Asian-ancestry lung adenocarcinoma (LUAD) and revealed lower frequencies of altered driver genes on both somatic mutations and CNV levels, including EGFR, KRAS and ERRB2, in FLAC. Mutational signature analysis showed an enrichment of age-related mutational signatures in FLAC and tobacco-associated and defective DNA mismatch repair-related signatures were more enriched in H-FLAC and in L-FLAC, respectively. Significant differences between H-FLAC and L-FLAC were observed in the genomic and epigenomic landscape. In contrast, the transcriptomic landscape of H-FLAC closely dissembled L-FLAC by pathway enrichment analysis of differentially expressed genes. Furthermore, although genetic and epigenetic changes showed congruent evolutionary trajectories, the relationships between multi-level intratumor heterogeneity (ITH) were distinct in H-FLAC and L-FLAC. The genetic and transcriptional ITH showed a significant negative correlation in H-FLAC but a significant positive correlation in L-FLAC. Moreover, the lower genetic ITH was significantly related to a worse recurrence-free survival and overall survival in FLAC patients whereas lower methylation ITH H-FLAC patients tended to have better survival. Conclusions: In this study, we first depicted the multi-omics landscapes of this rare lung cancer type and compared the two subtypes in a multi-omics and heterogeneity aspect. Different levels of ITH showed different relationships with survival, and non-genetic ITH, instead of genetic ITH, may contribute to the prognosis in FLAC patients. Citation Format: Wei Guo, Li Sun, Xiaoxi Chen, Haitao Zhou, Shi Yan, Gang Zhao, Haimeng Tang, Hua Bao, Xue Wu, Yang Shao, Lin Lin. Multi-omics analysis of molecular landscape and heterogeneity in fe