title: microRNA classifiers are powerful diagnostic/prognostic tools in ALK-, EGFR-, and KRAS-driven lung cancers.
abstract: microRNAs (miRNAs) can act as oncosuppressors or oncogenes, induce chemoresistance or chemosensitivity, and are major posttranscriptional gene regulators. Anaplastic lymphoma kinase (ALK), EGF receptor (EGFR), and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are major drivers of non-small cell lung cancer (NSCLC). The aim of this study was to assess the miRNA profiles of NSCLCs driven by translocated ALK, mutant EGFR, or mutant KRAS to find driver-specific diagnostic and prognostic miRNA signatures. A total of 85 formalin-fixed, paraffin-embedded samples were considered: 67 primary NSCLCs and 18 matched normal lung tissues. Of the 67 primary NSCLCs, 17 were echinoderm microtubule-associated protein-like 4-ALK translocated (ALK(+)) lung cancers; the remaining 50 were not (ALK(-)). Of the 50 ALK(-) primary NSCLCs, 24 were EGFR and KRAS mutation-negative (i.e., WT; triple negative); 11 were mutant EGFR (EGFR(+)), and 15 were mutant KRAS (KRAS(+)). We developed a diagnostic classifier that shows how miR-1253, miR-504, and miR-26a-5p expression levels can classify NSCLCs as ALK-translocated, mutant EGFR, or mutant KRAS versus mutation-free. We also generated a prognostic classifier based on miR-769-5p and Let-7d-5p expression levels that can predict overall survival. This classifier showed better performance than the commonly used classifiers based on mutational status. Although it has several limitations, this study shows that miRNA signatures and classifiers have great potential as powerful, cost-effective next-generation tools to improve and complement current genetic tests. Further studies of these miRNAs can help define their roles in NSCLC biology and in identifying best-performing chemotherapy regimens.
authors.affiliation: Comprehensive Cancer Center, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: Lymphoma and Genomics Research Program, Institute of Oncology Research, CH-6500 Bellinzona, Switzerland;
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.affiliation: Department of Oncology, Tuscan Tumor Institute (ITT), 57100 Livorno, Italy;
authors.forename: Lorenza
authors.initials: L
authors.lastname: Landi
authors.affiliation: Comprehensive Cancer Center, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Stefania
authors.initials: S
authors.lastname: Carasi
authors.affiliation: Comprehensive Cancer Center, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210;
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.affiliation: Department of Oncology, Tuscan Tumor Institute (ITT), 57100 Livorno, Italy;
authors.forename: Carmelo
authors.initials: C
authors.lastname: Tibaldi
authors.affiliation: University Hospital of Pisa, 56126 Pisa, Italy;
authors.forename: Greta
authors.initials: G
authors.lastname: Alì
authors.affiliation: Department of Oncology, Tuscan Tumor Institute (ITT), 57100 Livorno, Italy;
authors.forename: Armida
authors.initials: A
authors.lastname: D'Incecco
authors.affiliation: Department of Oncology, Tuscan Tumor Institute (ITT), 57100 Livorno, Italy;
authors.forename: Gabriele
authors.initials: G
authors.lastname: Minuti
authors.affiliation: University Hospital of Pisa, 56126 Pisa, Italy;
authors.forename: Antonio
authors.initials: A
authors.lastname: Chella
authors.affiliation: University Hospital of Pisa, 56126 Pisa, Italy;
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
authors.affiliation: Department of General Anatomic Pathology, University of Padua, 35100 Padova, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Department of Oncology, Tuscan Tumor Institute (ITT), 57100 Livorno, Italy; carlo.croce@osumc.edu f.cappuzzo@gmail.com.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.affiliation: Comprehensive Cancer Center, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210; carlo.croce@osumc.edu f.cappuzzo@gmail.com.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000145:classification / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000145:classification / Q000235:genetics; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
chemical_list: C117307:KRAS protein, human; D035683:MicroRNAs; D012334:RNA, Neoplasm; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: EGFR; EML4-ALK; KRAS; lung cancer; microRNAs