expression and DNA homologous recombination repair factors in lung cancers with a high-grade fetal adenocarcinoma component.

BACKGROUND

High-grade fetal adenocarcinoma of the lung (H-FLAC) is a rare variant of pulmonary adenocarcinoma. Our previous study showed a high frequency of KMT2C mutations in lung cancers with an H-FLAC component, showing that KMT2C dysfunction may be associated with the biological features of H-FLACs.

METHODS

In this study, we performed RNA sequencing and immunohistochemical analysis to identify the differentially expressed genes and corresponding pathways associated with H-FLACs, compared with common adenocarcinomas.

RESULTS

Ingenuity pathway analysis based on RNA sequencing data revealed that DNA homologous recombination repair (HRR) pathways were significantly inactivated in H-FLAC. Expression of , and was significantly lower in H-FLACs than in common adenocarcinomas, and expression showed a decreasing trend. Pearson correlation analyses for all cases revealed that expression showed a strong positive correlation (R>0.7) with the expression of , and genes and a moderately positive correlation with expression (R=0.47). Immunohistochemical analysis showed significantly lower levels of KMT2C, ATM, ATR, and BRCA2 expression in H-FLACs than in common adenocarcinomas, and a trend of lower BRCA1 levels. Additionally, KMT2C expression showed a weak to moderate correlation with that of ATM, ATR, BRCA1, and BRCA2.

CONCLUSIONS

Cancers containing H-FLAC components showed lower levels of KMT2C and HRR factors than common lung adenocarcinomas, and their levels exhibited a positive correlation. These results support the hypothesis that loss of KMT2C function decreases the expression of the HRR factors in H-FLACs. H-FLACs with low expression may be a good indication for poly (ADP-ribose) polymerase (PARP) inhibitor-based therapy.