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

Abstract 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. In this study, we first depicted the multi-omics landscapes of this rare lung cancer type by performing multi-regional whole-exome sequencing, DNA methylation sequencing and RNA sequencing on 20 FLAC cases. Comparison of multi-omics profiles revealed significant differences between H-FLAC and L-FLAC in the genomic, epigenomic landscape and mutational signature but the transcriptomic landscape. Although phylogenetic analysis showed congruent evolutionary trajectories of the genetic and epigenetic change, the correlative relationships among multi-level intratumor heterogenetic (ITH) were distinct in two subtypes. A lower genetic ITH was related to worse prognosis in FLAC patients whereas higher methylation ITH in H-FLAC tended to relate to a worse survival. Taken together with the negative correlation between genetic and transcriptional ITH of H-FLAC, non-genetic heterogeneity may contribute to the worse prognosis of H-FLAC.