Molecular heterogeneity in histomorphologic subtypes of lung adeno carcinoma represents a challenge for treatment decision.

Lung cancer is the leading cause in cancer related death, with non-small cell lung cancer (NSCLC) being the most frequent subtype. The importance of NSCLC is reflected by the various targeted therapy options especially for NSCLC adenocarcinomas (lung adeno carcinoma (LUAD)) as well as a set of options for immune therapies. However, despite these therapy advances, the majority of patients do not show a long-term response to either targeted therapy or immune checkpoint inhibition. One reason for treatment failure appears to be the NSCLC tumor heterogeneity. NSCLC heterogeneity might lead to an insufficient molecular characterization of a given sample due to the limited tumor material used for pathological assessment as the majority of analyses is performed on small biopsies. To get a more detailed insight into the tumor heterogeneity of NSCLC LUAD, especially in the light of its different histomorphological growth patterns, we analysed isolated NSCLC growth pattern areas and the corresponding entire tumor samples of a cohort of 31 NSLCS LUAD patients and compared their mutational landscape and their expression profiles. While significant differences of complex biomarkers, like tumor mutational burden (TMB) or microsatellite instability (MSI), were not detected between the five growth patterns -lepidic, papillary, micropapillary, acinar, and solid- we observed various subclonal mutations and copy number variants. Moreover, RNASeq analysis revealed growth pattern specific expression profiles affecting cellular processes like apoptosis, metastasis and proliferation. Taken together, our data provide novel insights into the tumor heterogeneity of LUAD required to overcome tumor heterogeneity related therapy resistance.