title: APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma.
abstract: Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here, we report wide variation in the expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in the majority of ovarian cancer cell lines (three SDs above the mean of normal ovarian surface epithelial cells) and high-grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5'-TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5'-TC dinucleotide motifs in early-stage high-grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA "repair" enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability.
authors.affiliation: Authors' Affiliations: Biochemistry, Molecular Biology and Biophysics Department; Masonic Cancer Center, University of Minnesota, Minneapolis; Division of Biomedical Statistics and Informatics, Department of Health Sciences Research; Medical Genome Facility and Department of Laboratory Medicine and Pathology; Department of Laboratory Medicine and Pathology; Division of Medical Oncology, Department of Oncology; Division of Epidemiology, Department of Health Sciences Research; Division of Oncology Research, Department of Oncology; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic; Women's Cancer Program, Mayo Clinic Cancer Center, Rochester, Minnesota; Department of Cancer Biology, University of Kansas, Kansas City, Kansas; Department of Obstetrics & Gynecology, University of Washington School of Medicine, Seattle, Washington; and Illumina Cambridge Ltd, Chesterford Research Park, Little Chesterford, Cambridge, United Kingdom.
authors.forename: Brandon
authors.initials: B
authors.lastname: Leonard
authors.forename: Steven N
authors.initials: SN
authors.lastname: Hart
authors.forename: Michael B
authors.initials: MB
authors.lastname: Burns
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carpenter
authors.forename: Nuri A
authors.initials: NA
authors.lastname: Temiz
authors.forename: Anurag
authors.initials: A
authors.lastname: Rathore
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Vogel
authors.forename: Jason B
authors.initials: JB
authors.lastname: Nikas
authors.forename: Emily K
authors.initials: EK
authors.lastname: Law
authors.forename: William L
authors.initials: WL
authors.lastname: Brown
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Yuji
authors.initials: Y
authors.lastname: Zhang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maurer
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.forename: Debra A
authors.initials: DA
authors.lastname: Bell
authors.forename: Craig
authors.initials: C
authors.lastname: April
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.forename: R Keira
authors.initials: RK
authors.lastname: Cheetham
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.forename: Russell
authors.initials: R
authors.lastname: Grocock
authors.forename: Sean
authors.initials: S
authors.lastname: Humphray
authors.forename: Zoya
authors.initials: Z
authors.lastname: Kingsbury
authors.forename: John
authors.initials: J
authors.lastname: Peden
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Hartmann
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.forename: Hugues
authors.initials: H
authors.lastname: Sicotte
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D023281:Genomics; D006801:Humans; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase