Reactivation of Multiple Fetal miRNAs in Lung Adenocarcinoma

Author(s):Show less -

Cohn, David E. ^[1] ; Barros-Filho, Mateus C. ^{[1, 2]} ; Minatel, Brenda C. ^[1] ; Pewarchuk, Michelle E. ^[1] ; Marshall, Erin A. ^[1] ; Vucic, Emily A. ^{[1, 3]} ; Sage, Adam P. ^[1] ; Telkar, Nikita ^{[1, 4, 5]} ; Stewart, Greg L. ^[1] ; Jurisica, Igor ^{[6, 7, 8, 9]} ; Reis, Patricia P. ^[10] ; Robinson, Wendy P. ^{[4, 5]} ; Lam, Wan L. ^[1]

Affiliation

^[1] British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3 - Canada

^[2] AC Camargo Canc Ctr, Int Res Ctr, BR-01525001 Sao Paulo, SP - Brazil

^[3] NYU, Langone Med Ctr, New York, NY 10016 - USA

^[4] British Columbia Childrens Hosp, Res Inst, Vancouver, BC V5Z 4H4 - Canada

^[5] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1 - Canada

^[6] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7 - Canada

^[7] Univ Hlth Network, Schroeder Arthrit Inst, Div Orthoped Surg, Osteoarthrit Res Program, Toronto, ON M5T 0S8 - Canada

^[8] Univ Hlth Network, Krembil Res Inst, Data Sci Discovery Ctr Chron Dis, Toronto, ON M5T 0S8 - Canada

^[9] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 2E4 - Canada

^[10] Sao Paulo State Univ UNESP, Fac Med, BR-18618687 Botucatu, SP - Brazil

• Document type: Journal article
• Source: CANCERS; v. 13, n. 11 JUN 2021.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 18/06138-8 - Small non-coding RNA as master regulators in thyroid cancer
• Grantee: Mateus de Camargo Barros Filho
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor