APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma

Brandon Leonard, Steven N. Hart, Michael B. Burns, Michael A. Carpenter, Nuri A. Temiz, Anurag Rathore, Rachel I. Vogel, Jason B. Nikas, Emily K. Law, William L. Brown, Ying Li, Yuji Zhang, Matthew J. Maurer, Ann L. Oberg, Julie M. Cunningham, Viji Shridhar, Debra A. Bell, Craig April, David Bentley, Marina BibikovaR. Keira Cheetham, Jian Bing Fan, Russell Grocock, Sean Humphray, Zoya Kingsbury, John Peden, Jeremy Chien, Elizabeth M. Swisher, Lynn C. Hartmann, Kimberly R. Kalli, Ellen L. Goode, Hugues Sicotte, Scott H. Kaufmann, Reuben S. Harris

Research output: Contribution to journalArticle

90 Citations (Scopus)

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 50-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 50-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.

Original languageEnglish (US)
Pages (from-to)7222-7231
Number of pages10
JournalCancer Research
Volume73
Issue number24
DOIs
StatePublished - Dec 15 2013

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Ovarian Neoplasms
Up-Regulation
Carcinoma
Mutation
Cytosine Deaminase
Genome
DNA Repair Enzymes
Cell Line
Deamination
Uracil
Genomic Instability
Cytosine
Epithelial Cells
DNA

Cite this

APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma. / 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.

In: Cancer Research, Vol. 73, No. 24, 15.12.2013, p. 7222-7231.

Research output: Contribution to journalArticle

Leonard, B, Hart, SN, Burns, MB, Carpenter, MA, Temiz, NA, Rathore, A, Vogel, RI, Nikas, JB, Law, EK, Brown, WL, Li, Y, Zhang, Y, Maurer, MJ, Oberg, AL, Cunningham, JM, Shridhar, V, Bell, DA, April, C, Bentley, D, Bibikova, M, Cheetham, RK, Fan, JB, Grocock, R, Humphray, S, Kingsbury, Z, Peden, J, Chien, J, Swisher, EM, Hartmann, LC, Kalli, KR, Goode, EL, Sicotte, H, Kaufmann, SH & Harris, RS 2013, 'APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma', Cancer Research, vol. 73, no. 24, pp. 7222-7231. https://doi.org/10.1158/0008-5472.CAN-13-1753
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. / APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma. In: Cancer Research. 2013 ; Vol. 73, No. 24. pp. 7222-7231.
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T1 - APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma

AU - Leonard, Brandon

AU - Hart, Steven N.

AU - Burns, Michael B.

AU - Carpenter, Michael A.

AU - Temiz, Nuri A.

AU - Rathore, Anurag

AU - Vogel, Rachel I.

AU - Nikas, Jason B.

AU - Law, Emily K.

AU - Brown, William L.

AU - Li, Ying

AU - Zhang, Yuji

AU - Maurer, Matthew J.

AU - Oberg, Ann L.

AU - Cunningham, Julie M.

AU - Shridhar, Viji

AU - Bell, Debra A.

AU - April, Craig

AU - Bentley, David

AU - Bibikova, Marina

AU - Cheetham, R. Keira

AU - Fan, Jian Bing

AU - Grocock, Russell

AU - Humphray, Sean

AU - Kingsbury, Zoya

AU - Peden, John

AU - Chien, Jeremy

AU - Swisher, Elizabeth M.

AU - Hartmann, Lynn C.

AU - Kalli, Kimberly R.

AU - Goode, Ellen L.

AU - Sicotte, Hugues

AU - Kaufmann, Scott H.

AU - Harris, Reuben S.

PY - 2013/12/15

Y1 - 2013/12/15

N2 - 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 50-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 50-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.

AB - 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 50-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 50-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.

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