title: Diverse repetitive element RNA expression defines epigenetic and immunologic features of colon cancer.
abstract: There is tremendous excitement for the potential of epigenetic therapies in cancer, but the ability to predict and monitor response to these drugs remains elusive. This is in part due to the inability to differentiate the direct cytotoxic and the immunomodulatory effects of these drugs. The DNA-hypomethylating agent 5-azacitidine (AZA) has shown these distinct effects in colon cancer and appears to be linked to the derepression of repeat RNAs. LINE and HERV are two of the largest classes of repeats in the genome, and despite many commonalities, we found that there is heterogeneity in behavior among repeat subtypes. Specifically, the LINE-1 and HERV-H subtypes detected by RNA sequencing and RNA in situ hybridization in colon cancers had distinct expression patterns, which suggested that these repeats are correlated to transcriptional programs marking different biological states. We found that low LINE-1 expression correlates with global DNA hypermethylation, wild-typeTP53status, and responsiveness to AZA. HERV-H repeats were not concordant with LINE-1 expression but were found to be linked with differences in FOXP3+Treg tumor infiltrates. Together, distinct repeat RNA expression patterns define new molecular classifications of colon cancer and provide biomarkers that better distinguish cytotoxic from immunomodulatory effects by epigenetic drugs.
authors.affiliation: Massachusetts General Hospital Cancer Center.|Department of Pathology, and.
authors.forename: Niyati
authors.initials: N
authors.lastname: Desai
authors.affiliation: Department of Pathology, and.
authors.forename: Dipti
authors.initials: D
authors.lastname: Sajed
authors.affiliation: Massachusetts General Hospital Cancer Center.|Department of Pathology, and.|Department of Surgery, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Kshitij S
authors.initials: KS
authors.lastname: Arora
authors.affiliation: Tisch Cancer Institute, Department of Medicine, Hematology and Medical Oncology, Department of Oncological Sciences, and Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Solovyov
authors.affiliation: Massachusetts General Hospital Cancer Center.
authors.forename: Mihir
authors.initials: M
authors.lastname: Rajurkar
authors.affiliation: Department of Pathology, and.
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Bledsoe
authors.affiliation: Massachusetts General Hospital Cancer Center.
authors.forename: Srinjoy
authors.initials: S
authors.lastname: Sil
authors.affiliation: Department of Surgery, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Amri
authors.affiliation: Massachusetts General Hospital Cancer Center.
authors.forename: Eric
authors.initials: E
authors.lastname: Tai
authors.affiliation: Massachusetts General Hospital Cancer Center.
authors.forename: Olivia C
authors.initials: OC
authors.lastname: MacKenzie
authors.affiliation: Department of Pathology, and.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Massachusetts General Hospital Cancer Center.|Department of Pathology, and.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Aryee
authors.affiliation: Department of Surgery, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.affiliation: Department of Surgery, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Berger
authors.affiliation: Massachusetts General Hospital Cancer Center.|Department of Pathology, and.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.affiliation: Tisch Cancer Institute, Department of Medicine, Hematology and Medical Oncology, Department of Oncological Sciences, and Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Greenbaum
authors.affiliation: Department of Pathology, and.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Massachusetts General Hospital Cancer Center.|Department of Medicine, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
mesh_terms: D000368:Aged; D001374:Azacitidine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012091:Repetitive Sequences, Nucleic Acid / Q000187:drug effects; D017423:Sequence Analysis, RNA / Q000379:methods
chemical_list: D001374:Azacitidine