APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 24; pp. 7222 - 7231
• Main Authors: Leonard, Brandon, Hart, Steven N, Burns, Michael B, Carpenter, Michael A, Temiz, Nuri A, Rathore, Anurag, Vogel, Rachel I, Nikas, Jason B, Law, Emily K, Brown, William L, Li, Ying, Zhang, Yuji, Maurer, Matthew J, Oberg, Ann L, Cunningham, Julie M, Shridhar, Viji, Bell, Debra A, April, Craig, Bentley, David, Bibikova, Marina, Cheetham, R Keira, Fan, Jian-Bing, Grocock, Russell, Humphray, Sean, Kingsbury, Zoya, Peden, John, Chien, Jeremy, Swisher, Elizabeth M, Hartmann, Lynn C, Kalli, Kimberly R, Goode, Ellen L, Sicotte, Hugues, Kaufmann, Scott H, Harris, Reuben S
• Format: Journal Article
• Language: English
• Published: United States 15.12.2013
• Subjects: Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cystadenocarcinoma, Serous - enzymology; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - pathology; Cytidine Deaminase - biosynthesis; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genomics; Humans; Minor Histocompatibility Antigens; Mutation; Neoplasms, Glandular and Epithelial - enzymology; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - pathology; Ovarian Neoplasms - enzymology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Up-Regulation
• DOI: 10.1158/0008-5472.can-13-1753
• ISSN: 0008-5472

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.