Reactivation of Multiple Fetal miRNAs in Lung Adenocarcinoma

Simple Summary Patterns of microRNA expression in fetal tissues are not well-characterized, due to the rarity of human fetal samples. Characterization of these patterns is vital for improving our understanding of developmental disorders, and can also provide insights into cancer development, as tumours frequently exploit developmental pathways to facilitate their uncontrolled growth. To profile fetal microRNA expression, we compared the small RNA transcriptomes of a unique cohort of 25 fetal lung samples and two independent cohorts of adult lung specimens, each containing adenocarcinoma and non-malignant samples. We identified 13 'oncofetal' microRNAs that were highly expressed in the fetal and adenocarcinoma samples but absent from the adult non-malignant samples. These microRNAs showed potential as markers for cancer detection, and the expression of three of them was associated with shorter survival times for lung adenocarcinoma patients. The absence of these microRNAs from the non-malignant adult lung also makes them compelling targets for novel therapies. MicroRNAs (miRNAs) play vital roles in the regulation of normal developmental pathways. However, cancer cells can co-opt these miRNAs, and the pathways that they regulate, to drive pro-tumourigenic phenotypes. Characterization of the miRNA transcriptomes of fetal organs is essential for identifying these oncofetal miRNAs, but it has been limited by fetal sample availability. As oncofetal miRNAs are absent from healthy adult lungs, they represent ideal targets for developing diagnostic and therapeutic strategies. We conducted small RNA sequencing of a rare collection of 25 human fetal lung (FL) samples and compared them to two independent cohorts (n = 140, n = 427), each comprised of adult non-neoplastic lung (ANL) and lung adenocarcinoma (LUAD) samples. We identified 13 oncofetal miRNAs that were expressed in FL and LUAD but not in ANL. These oncofetal miRNAs are potential biomarkers for LUAD detection (AUC = 0.963). Five of these miRNAs are derived from the imprinted C14MC miRNA cluster at the 14q32 locus, which has been associated with cancer development and abnormal fetal and placental development. Additionally, we observed the pulmonary expression of 44 previously unannotated miRNAs. The sequencing of these fetal lung samples also provides a baseline resource against which aberrant samples can be compared.