Browsing by Author "Fabris, Linda"

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    Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations
    (Cold Spring Harbor Laboratory Press, 2018-04) Shah, Maitri Y.; Ferracin, Manuela; Pileczki, Valentina; Chen, Baoqing; Redis, Roxana; Fabris, Linda; Zhang, Xinna; Ivan, Cristina; Shimizu, Masayoshi; Rodriguez-Aguayo, Cristian; Dragomir, Mihnea; Van Roosbroeck, Katrien; Almeida, Maria Ines; Ciccone, Maria; Nedelcu, Daniela; Cortez, Maria Angelica; Manshouri, Taghi; Calin, Steliana; Muftuoglu, Muharrem; Banerjee, Pinaki P.; Badiwi, Mustafa H.; Parker-Thornburg, Jan; Multani, Asha; Welsh, James William; Estecio, Marcos Roberto; Ling, Hui; Tomuleasa, Ciprian; Dima, Delia; Yang, Hui; Alvarez, Hector; You, M. James; Radovich, Milan; Shpall, Elizabeth; Fabbri, Muller; Rezvani, Katy; Girnita, Leonard; Berindan-Neagoe, Ioana; Maitra, Anirban; Verstovsek, Srdan; Foddle, Riccardo; Bueso-Ramos, Carlos; Gagea, Mihai; Manero, Guillermo Garcia; Calin, Goerge A.; BioHealth Informatics, School of Informatics and Computing
    The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNA CCAT2 in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. We further identified that CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by down-regulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel non-APOBEC, non-ADAR, RNA editing at the SNP locus in MDS/MPN patients and CCAT2-transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies.
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    The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers
    (American Association for the Advancement of Science, 2025) Bayraktar, Recep; Tang, Yitao; Dragomir, Mihnea P.; Ivan, Cristina; Peng, Xinxin; Fabris, Linda; Zhang, Jianhua; Carugo, Alessandro; Aneli, Serena; Liu, Jintan; Chen, Mei-Ju M.; Srinivasan, Sanjana; Sahnoune, Iman; Bayraktar, Emine; Akdemir, Kadir C.; Chen, Meng; Narayanan, Pranav; Huang, Wilson; Ott, Leonie Florence; Eterovic, Agda Karina; Villarreal, Oscar Eduardo; Mohammad, Mohammad Moustaf; Peoples, Michael D.; Walsh, Danielle M.; Hernandez, Jon Andrew; Morgan, Margaret B.; Shaw, Kenna R.; Davis, Jennifer S.; Menter, David; Tam, Constantine S.; Yeh, Paul; Dawson, Sarah-Jane; Rassenti, Laura Z.; Kipps, Thomas J.; Kunej, Tanja; Estrov, Zeev; Joosse, Simon A.; Pagani, Luca; Alix-Panabières, Catherine; Pantel, Klaus; Ferajoli, Alessandra; Futreal, Andrew; Wistuba, Ignacio I.; Radovich, Milan; Kopetz, Scott; Keating, Michael J.; Draetta, Giulio F.; Mattick, John S.; Liang, Han; Calin, George A.; Surgery, School of Medicine
    The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNAs (ncUCEs), and their functional relevance in cancers remain poorly characterized. Here, we perform a systematic analysis of whole-genome and in-house targeted UCE sequencing datasets from more than 3000 patients with cancer of 13,736 UCEs and demonstrate that ncUCE somatic alterations are common. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly affects cell proliferation. In-depth functional studies in vitro and in vivo further reveal that specific ncUCEs can be enhancers of tumor suppressors (such as ARID1B) and silencers of oncogenic proteins (such as RPS13). Moreover, several miRNAs located in ncUCEs are recurrently mutated. Mutations in miR-142 locus can affect the Drosha-mediated processing of precursor miRNAs, resulting in the down-regulation of the mature transcript. These results provide systematic evidence that specific ncUCEs play diverse regulatory roles in cancer.