title: Pericentromeric satellite repeat expansions through RNA-derived DNA intermediates in cancer.
abstract: Aberrant transcription of the pericentromeric human satellite II (HSATII) repeat is present in a wide variety of epithelial cancers. In deriving experimental systems to study its deregulation, we observed that HSATII expression is induced in colon cancer cells cultured as xenografts or under nonadherent conditions in vitro, but it is rapidly lost in standard 2D cultures. Unexpectedly, physiological induction of endogenous HSATII RNA, as well as introduction of synthetic HSATII transcripts, generated cDNA intermediates in the form of DNA/RNA hybrids. Single molecule sequencing of tumor xenografts showed that HSATII RNA-derived DNA (rdDNA) molecules are stably incorporated within pericentromeric loci. Suppression of RT activity using small molecule inhibitors reduced HSATII copy gain. Analysis of whole-genome sequencing data revealed that HSATII copy number gain is a common feature in primary human colon tumors and is associated with a lower overall survival. Together, our observations suggest that cancer-associated derepression of specific repetitive sequences can promote their RNA-driven genomic expansion, with potential implications on pericentromeric architecture.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;
authors.forename: Francesca
authors.initials: F
authors.lastname: Bersani
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115; Hematology/Oncology Program, Children's Hospital, Boston, MA 02115;
authors.forename: Peter V
authors.initials: PV
authors.lastname: Kharchenko
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115;
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Xu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Howard Hughes Medical Institute, Chevy Chase, MD 20815;
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Liu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;
authors.forename: Kristina
authors.initials: K
authors.lastname: Xega
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;
authors.forename: Olivia C
authors.initials: OC
authors.lastname: MacKenzie
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;
authors.forename: Brian W
authors.initials: BW
authors.lastname: Brannigan
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;
authors.forename: Ben S
authors.initials: BS
authors.lastname: Wittner
authors.affiliation: Samsung Medical Center, Seoul 135-710, Korea;
authors.forename: Hyunchul
authors.initials: H
authors.lastname: Jung
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115; Informatics Program, Children's Hospital, Boston, MA 02115;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114; dting1@mgh.harvard.edu dhaber@mgh.harvard.edu.
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Howard Hughes Medical Institute, Chevy Chase, MD 20815; Department of Medicine, Massachusetts General Hospital, Boston, MA 02114; dting1@mgh.harvard.edu dhaber@mgh.harvard.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D002503:Centromere / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D004276:DNA, Satellite / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D012313:RNA / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D004276:DNA, Satellite; D012313:RNA
keywords: cancer; repeats; reverse transcription; satellites