Tumor Biol. DOI 10.1007/s13277-014-1758-7
RESEARCH ARTICLE
APOBEC3 deletion polymorphism is associated with epithelial ovarian cancer risk among Chinese women Guannan Qi & Huijuan Xiong & Changju Zhou
Received: 26 January 2014 / Accepted: 13 February 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Ovarian cancer remains the leading cause of death from gynecological malignancies and the second most common gynecological malignancy among women worldwide. However, the etiology still remains largely unknown. Previous studies identified APOBEC3 gene deletions were significantly associated with higher breast cancer risk in both European and Chinese women. Considering both breast and ovarian cancers being hormonally driven and sharing multiple risk factors, we performed this case–control study to evaluate the association between APOBEC3 deletion and epithelial ovarian cancer (EOC) risk. We analyzed the APOBEC3 deletion in a case–control study of 2,938 Chinese women (including 1,374 EOC cases and 1,564 healthy controls). All participants were genotyped using real-time qualitative PCR (qPCR). APOBEC3 deletion was significant associated with EOC risk, with ORs (95 % CIs) of 1.46 (1.14–1.86) associated with one copy deletion and 2.53 (0.91–7.06) associated with two copy deletion compared with subjects with no deletion (P for trend =1.50×10−3). Additional adjustments and stratified analyses did not change the results materially. Our data suggests that the loss genotypes of APOBEC3 deletion predispose their carriers to EOC. Keywords Ovarian cancer . APOBEC3 . CNV . Genetic susceptibility
family history, genetic factors, diet, inflammation, and reproductive factors such as null-parity and oral contraceptive use, obesity, the etiology of ovarian cancer, remains poorly understood [3–8]. Studies showed that copy number variations (CNVs) could explain some of the missing heritability for complex traits after the genome-wide association study GWAS [9]. This variation accounts for roughly 12 % of human genomic DNA, and each variation may range from about 1 kb (1,000 nucleotide bases) to several megabases in size [10]. Recently, through CNV GWAS, Long et al. [11] discovered a common CNV locus for breast cancer in Chinese women, which was located between the fifth exon of APOBEC3A and the eighth exon of APOBEC3B. The result was also replicated among women of European ancestry [12]. Additional evidence has also implicated APOBEC3 as a source of mutations in cervical, bladder, lung, hepatocellular, head, and neck cancers [13–15]. Considering the potential function of APOBEC3 gene in the process of tumorigenesis, as well as both breast and ovarian cancers being hormonally driven and sharing multiple risk factors, it is possible that CNVs in this gene are responsible for epithelial ovarian cancer (EOC) risk. To test this hypothesis, we performed this population-based case–control study among Chinese women.
Materials and methods Introduction Subjects Ovarian cancer remains the leading cause of death from gynecological malignancies and the second most common gynecological malignancy among women worldwide [1, 2]. Although shown to be associated with hormonal factors, G. Qi : H. Xiong : C. Zhou (*) Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, Tongzi Po Road no. 138, Changsha 410013, China e-mail: [email protected]
Subjects participating in this study were ethnically homogenous Han Chinese. Cases were 1,374 pathologically confirmed EOC patients recruited through the Cancer and Vital Statistics Registries between October 2006 and October 2012, while controls were 1,564 healthy subjects which were frequency-matched to the cases by age (within 5 years old), geography location, and residential area (urban or countryside). Histological subtypes of ovarian cancer were classified
Tumor Biol.
according to International Classification of Diseases for Oncology (ICD-O) codes. The controls had no known history of cancers or benign ovary diseases. Each subject was interviewed face to face by trained personnel using a formatted questionnaire to obtain demographic data and overall health characteristics. After the interview, each subject provided 3–5 mL of venous blood. Approval for this study was obtained from the institutional review board. A written informed consent was obtained from all participants or from the patients’ representatives. Copy number analyses Genomic DNA was extracted from 2 ml whole blood of each participant. The final concentrations of all DNA samples were 20 ng/ml with good purity (OD260/OD280=1.8–2.0). According to the protocol of Applied Biosystems, copy number analyses for all subjects were conducted using real-time qualitative PCR (qPCR). Primers and probes for the gene APOBEC3 and the reference gene were purchased from Applied Biosystems (ABI). Each 96-well plate included one negative control (water) and two samples from the HapMap project as quality control (QC) samples. All qPCR assays were performed by a single lab staff member, and all CNV calls were conducted by two independent staff members.
were serous, 110 (8 %) were mucinous, 54 (4 %) were clear cell, and 138 (10 %) were endometrioid, while 110 (8 %) were others. A highly significant association was observed between the APOBEC3 deletion and EOC risk, with ORs (95 % CIs) of 1.46 (1.14–1.86) associated with one copy deletion and 2.53 (0.91–7.06) associated with two copy deletion compared with subjects with no deletion (P for trend =1.50×10−3, Table 2). After adjusting for additional potentially confounding factors such as education, body mass index, hormone replacement therapy, and ever smoking, the results did not change materially. The ORs (95 % CIs) of 1.46 (1.13–1.87) associated with one copy deletion and 2.52 (0.93 – 6.87) associated with two copy deletion compared with subjects with no deletion (P for trend =8.84×10−3, Table 2). Further, possible modifications of the surrounding factors were evaluated by stratified analyses (data not shown). The positive association of the APOBEC3 deletion with EOC risk was similar when stratified by age, education, body mass index, hormone replacement therapy, ever smoking, and histological subtypes. In addition, we did not find any significant interaction between the CNVand surrounding factors on EOC risk (data not shown).
Discussion Statistical analyses Characteristics of demographic data between cases and controls were compared with the chi-square or t test for categorical or continuous variables, respectively. Associations between the CNV and EOC risk were assessed using odds ratios (ORs) and 95 % confidence intervals (CIs) derived from logistic regression models. ORs were estimated for one copy and two copy deletion genotypes compared with no deletion genotype. The OR (95 % CI) was also estimated for per copy loss based on a log-additive model and adjusted for age. All statistical tests were two-sided, and a P value significance threshold of 0.05 was set. All analyses were conducted using SAS, version 9.2 (SAS Institute, Cary, NC).
Results Characteristics of the study population are shown in Table 1. Totally, 1,374 EOC cases and 1,564 healthy controls were included in this study. There were no significant differences in distribution of age, gender, education, smoking, use of hormone replacement therapy, and body mass index (BMI). Generally speaking, cases were slightly elder, higher educated, more likely to be smokers, and users of hormone replacement therapy, and have higher BMI. When stratified by histological subtypes, among the 1,374 EOC cases, 962 (70 %)
In this population-based case–control study, we observed a significant association between APOBEC3 deletion polymorphism and EOC risk. The association was similar when stratified by age, education, body mass index, hormone Table 1 Distribution of demographic characteristics for EOC cases and controls Category
Cases (N=1,374)
Controls (N=1,564)
P value
Age (year) Education (less than middle school) Ever smoker Use of hormone replacement therapy Body mass index (kg/m2) Histopathology Serous Mucinous Clear cell Endometrioid
50.6±7.6 538 (39.1 %)
50.3±7.0 578 (37.0 %)
0.431 0.386
204 (14.9 %) 56 (4.03 %)
224 (14.3 %) 44 (2.76 %)
0.776 0.183
23.8±3.5
23.6±3.4
0.267
Others
962 (70 %) 110 (8 %) 54 (4 %) 138 (10 %) 110 (8 %)
Continuous variables, mean values±standard deviation, P value from t tests; categorical variables, numbers and percentages, P values from x2 test
Tumor Biol. Table 2 Association between the APOBEC3 gene deletion and EOC risk a
Adjusted for age
b Adjusted for age, education, body mass index, hormone replacement therapy, and ever smoking
Genotypes Per copy deletion No deletion One copy deletion Two copy deletion Ptrend
No. of cases
No. of controls
1,374 1,010 342 22
1,564 1,254 300 10
replacement therapy, ever smoking, and histological subtypes. To the best of our knowledge, this should be the first study aiming to explore the association between CNVs of APOBEC3 gene and ovarian cancer risk. This provides evidence to implicate APOBEC3 gene deletion as a novel susceptibility factor for EOC risk. The APOBEC3 gene family, including APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3E, APOBEC3F, APOBEC3G, and APOBEC3H, plays pivotal roles in intracellular defense against viral infection [16, 17]. The APOBEC3 family of DNA-editing enzymes is thought to be part of the innate immune system by restricting retroviruses, mobile genetic elements like retro-transposons and endogenous retroviruses [18]. APOBEC3A gene, a member of the cytidine deaminase gene family, is located at 22q13.1q13.2. APOBEC3A exhibits antiviral activity against adenoassociated virus (AAV) and human T cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons [19]. The APOBEC3A gene could go towards explaining 5-methylcytidine mutation hotspots in cancer genomes [9]. APOBEC3B gene, which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and deaminase-independent mechanisms, is also located at 22q13.1-q13.2. Burns et al. identified APOBEC3B-catalyzed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumors evolve rapidly and manifest heterogeneity [20]; Very recently, Burns et al. screened 19 different cancer types by analyzing gene expression data and mutation patterns, distributions, and loads, and identified that its preferred target sequence is frequently mutated and clustered in at least six distinct cancers: bladder, cervix, lung (adenocarcinoma and squamous cell carcinoma), head and neck, and breast [14]; APOBEC3B were also confirmed to have a potential role in serous ovarian cancer genomic instability [21]. In current study, The APOBEC3 deletion, which is located between exon 5 of APOBEC3A gene and exon 8 of APOBEC3B gene and 29.5 kb in length, was explored for the possibility of being responsible for EOC risk among 1,374 EOC cases and 1,564 healthy controls. We first identified APOBEC3 gene deletion was significantly associated with increased EOC risk. As we know, CNVs can directly influence gene expression and phenotypic variation, disrupt gene
OR (95 % CI)a
OR (95 % CI)b
1.43 (1.15–1.79) 1.00 (reference) 1.46 (1.14–1.86) 2.53 (0.91–7.06) 1.50×10−3
1.44 (1.10–1.89) 1.00 (reference) 1.46 (1.13–1.87) 2.52 (0.93–6.87) 8.84×10−3
structure, alter gene dosage, and indirectly regulate gene function through position effects. Thus, the deletion in APOBEC3 gene may be a new biomarker for predicting EOC risk. Some limitations should be addressed in this study. First, as hospital-based case–control studies, the selection bias is unavoidable; since this study was restricted to a Chinese Han population, it is uncertain whether our findings can be replicated by other ethnic groups; and the statistical power of this study to perform interaction analyses between this deletion and known ovarian cancer risk factors is still limited. Further replication analyses and functional research may elucidate the finding that the CNV has significant association with EOC risk. In summary, this study found that the loss genotypes of APOBEC3 deletion were associated with an increased EOC risk in Chinese. The results suggest that the APOBEC3 deletion may be a new biomarker for EOC susceptibility. Validations with larger population-based studies in different ethnic groups, further research into the function of APOBEC3 deletion and its potential biological mechanism association may be warranted. Acknowledgments We thank all the staffs who were involved in the subject recruitment, telephone interviews, sample preparation, and laboratory assays for their hard works. Conflicts of interest None
References 1. Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Cl Ob. 2006;20:207–25. 2. Jemal A, Siegel R, Xu JQ, Ward E. Cancer statistics, 2010. CaCancer J Clin. 2010;60:277–300. 3. Holschneider CH, Berek JS. Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg Oncol. 2000;19:3–10. 4. Kurman RJ, Shih Ie M. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34:433–43. 5. Zheng W, Danforth KN, Tworoger SS, Goodman MT, Arslan AA, Patel AV, et al. Circulating 25-hydroxyvitamin d and risk of epithelial ovarian cancer: cohort consortium vitamin d pooling project of rarer cancers. Am J Epidemiol. 2010;172:70–80. 6. McLaughlin JR, Risch HA, Lubinski J, Moller P, Ghadirian P, Lynch H, et al. Reproductive risk factors for ovarian cancer in carriers of brca1 or brca2 mutations: a case–control study. Lancet Oncol. 2007;8:26–34.
Tumor Biol. 7. Shu XO, Dorjgochoo T, Li HL, Qian HZ, Yang G, Cai H, et al. Use of oral contraceptives, intrauterine devices and tubal sterilization and cancer risk in a large prospective study, from 1996 to 2006. Int J Cancer. 2009;124:2442–9. 8. Ma X, Beeghly-Fadiel A, Shu XO, Li H, Yang G, Gao YT, et al. Anthropometric measures and epithelial ovarian cancer risk among chinese women: results from the shanghai women’s health study. Br J Cancer. 2013;109:751–5. 9. Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet. 2010;11:446–50. 10. Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010;61:437–55. 11. Long J, Delahanty RJ, Li G, Gao YT, Lu W, Cai Q, et al. A common deletion in the apobec3 genes and breast cancer risk. J Natl Cancer Inst. 2013;105:573–9. 12. Xuan D, Li GL, Cai QY, Deming-Halverson S, Shrubsole MJ, Shu XO, et al. Apobec3 deletion polymorphism is associated with breast cancer risk among women of european ancestry. Carcinogenesis. 2013;34:2240–3. 13. Kuong KJ, Loeb LA. Apobec3b mutagenesis in cancer. Nat Genet. 2013;45:964–5. 14. Burns MB, Temiz NA, Harris RS. Evidence for apobec3b mutagenesis in multiple human cancers. Nat Genet. 2013;45:977–83. 15. Zhang T, Cai J, Chang J, Yu D, Wu C, Yan T, et al. Evidence of associations of apobec3b gene deletion with susceptibility to
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persistent hbv infection and hepatocellular carcinoma. Hum Mol Genet. 2013;22:1262–9. Chiu YL, Greene WC. The apobec3 cytidine deaminases: an innate defensive network opposing exogenous retroviruses and endogenous retroelements. Annu Rev Immunol. 2008;26:317–53. Wedekind JE, Dance GS, Sowden MP, Smith HC. Messenger RNA editing in mammals: new members of the apobec family seeking roles in the family business. Trends Genet. 2003;19:207–16. Stenglein MD, Burns MB, Li M, Lengyel J, Harris RS. Apobec3 proteins mediate the clearance of foreign DNA from human cells. Nat Struct Mol Biol. 2010;17:222–9. Holmes RK, Malim MH, Bishop KN. Apobec-mediated viral restriction: not simply editing? Trends Biochem Sci. 2007;32: 118–28. Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM, Leonard B, et al. Apobec3b is an enzymatic source of mutation in breast cancer. Nature. 2013;494:366–70. Leonard B, Hart SN, Burns MB, Carpenter MA, Temiz NA, Rathore A, Isaksson Vogel R, Nikas JB, Law EK, Brown WL, Li Y, Zhang Y, Maurer MJ, Oberg AL, Cunningham JM, Shridhar V, Bell DA, April C, Bently 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: Apobec3b upregulation and genomic mutation patterns in serous ovarian carcinoma. Cancer Res 2013
RESEARCH ARTICLE
APOBEC3 deletion polymorphism is associated with epithelial ovarian cancer risk among Chinese women Guannan Qi & Huijuan Xiong & Changju Zhou
Received: 26 January 2014 / Accepted: 13 February 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Ovarian cancer remains the leading cause of death from gynecological malignancies and the second most common gynecological malignancy among women worldwide. However, the etiology still remains largely unknown. Previous studies identified APOBEC3 gene deletions were significantly associated with higher breast cancer risk in both European and Chinese women. Considering both breast and ovarian cancers being hormonally driven and sharing multiple risk factors, we performed this case–control study to evaluate the association between APOBEC3 deletion and epithelial ovarian cancer (EOC) risk. We analyzed the APOBEC3 deletion in a case–control study of 2,938 Chinese women (including 1,374 EOC cases and 1,564 healthy controls). All participants were genotyped using real-time qualitative PCR (qPCR). APOBEC3 deletion was significant associated with EOC risk, with ORs (95 % CIs) of 1.46 (1.14–1.86) associated with one copy deletion and 2.53 (0.91–7.06) associated with two copy deletion compared with subjects with no deletion (P for trend =1.50×10−3). Additional adjustments and stratified analyses did not change the results materially. Our data suggests that the loss genotypes of APOBEC3 deletion predispose their carriers to EOC. Keywords Ovarian cancer . APOBEC3 . CNV . Genetic susceptibility
family history, genetic factors, diet, inflammation, and reproductive factors such as null-parity and oral contraceptive use, obesity, the etiology of ovarian cancer, remains poorly understood [3–8]. Studies showed that copy number variations (CNVs) could explain some of the missing heritability for complex traits after the genome-wide association study GWAS [9]. This variation accounts for roughly 12 % of human genomic DNA, and each variation may range from about 1 kb (1,000 nucleotide bases) to several megabases in size [10]. Recently, through CNV GWAS, Long et al. [11] discovered a common CNV locus for breast cancer in Chinese women, which was located between the fifth exon of APOBEC3A and the eighth exon of APOBEC3B. The result was also replicated among women of European ancestry [12]. Additional evidence has also implicated APOBEC3 as a source of mutations in cervical, bladder, lung, hepatocellular, head, and neck cancers [13–15]. Considering the potential function of APOBEC3 gene in the process of tumorigenesis, as well as both breast and ovarian cancers being hormonally driven and sharing multiple risk factors, it is possible that CNVs in this gene are responsible for epithelial ovarian cancer (EOC) risk. To test this hypothesis, we performed this population-based case–control study among Chinese women.
Materials and methods Introduction Subjects Ovarian cancer remains the leading cause of death from gynecological malignancies and the second most common gynecological malignancy among women worldwide [1, 2]. Although shown to be associated with hormonal factors, G. Qi : H. Xiong : C. Zhou (*) Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, Tongzi Po Road no. 138, Changsha 410013, China e-mail: [email protected]
Subjects participating in this study were ethnically homogenous Han Chinese. Cases were 1,374 pathologically confirmed EOC patients recruited through the Cancer and Vital Statistics Registries between October 2006 and October 2012, while controls were 1,564 healthy subjects which were frequency-matched to the cases by age (within 5 years old), geography location, and residential area (urban or countryside). Histological subtypes of ovarian cancer were classified
Tumor Biol.
according to International Classification of Diseases for Oncology (ICD-O) codes. The controls had no known history of cancers or benign ovary diseases. Each subject was interviewed face to face by trained personnel using a formatted questionnaire to obtain demographic data and overall health characteristics. After the interview, each subject provided 3–5 mL of venous blood. Approval for this study was obtained from the institutional review board. A written informed consent was obtained from all participants or from the patients’ representatives. Copy number analyses Genomic DNA was extracted from 2 ml whole blood of each participant. The final concentrations of all DNA samples were 20 ng/ml with good purity (OD260/OD280=1.8–2.0). According to the protocol of Applied Biosystems, copy number analyses for all subjects were conducted using real-time qualitative PCR (qPCR). Primers and probes for the gene APOBEC3 and the reference gene were purchased from Applied Biosystems (ABI). Each 96-well plate included one negative control (water) and two samples from the HapMap project as quality control (QC) samples. All qPCR assays were performed by a single lab staff member, and all CNV calls were conducted by two independent staff members.
were serous, 110 (8 %) were mucinous, 54 (4 %) were clear cell, and 138 (10 %) were endometrioid, while 110 (8 %) were others. A highly significant association was observed between the APOBEC3 deletion and EOC risk, with ORs (95 % CIs) of 1.46 (1.14–1.86) associated with one copy deletion and 2.53 (0.91–7.06) associated with two copy deletion compared with subjects with no deletion (P for trend =1.50×10−3, Table 2). After adjusting for additional potentially confounding factors such as education, body mass index, hormone replacement therapy, and ever smoking, the results did not change materially. The ORs (95 % CIs) of 1.46 (1.13–1.87) associated with one copy deletion and 2.52 (0.93 – 6.87) associated with two copy deletion compared with subjects with no deletion (P for trend =8.84×10−3, Table 2). Further, possible modifications of the surrounding factors were evaluated by stratified analyses (data not shown). The positive association of the APOBEC3 deletion with EOC risk was similar when stratified by age, education, body mass index, hormone replacement therapy, ever smoking, and histological subtypes. In addition, we did not find any significant interaction between the CNVand surrounding factors on EOC risk (data not shown).
Discussion Statistical analyses Characteristics of demographic data between cases and controls were compared with the chi-square or t test for categorical or continuous variables, respectively. Associations between the CNV and EOC risk were assessed using odds ratios (ORs) and 95 % confidence intervals (CIs) derived from logistic regression models. ORs were estimated for one copy and two copy deletion genotypes compared with no deletion genotype. The OR (95 % CI) was also estimated for per copy loss based on a log-additive model and adjusted for age. All statistical tests were two-sided, and a P value significance threshold of 0.05 was set. All analyses were conducted using SAS, version 9.2 (SAS Institute, Cary, NC).
Results Characteristics of the study population are shown in Table 1. Totally, 1,374 EOC cases and 1,564 healthy controls were included in this study. There were no significant differences in distribution of age, gender, education, smoking, use of hormone replacement therapy, and body mass index (BMI). Generally speaking, cases were slightly elder, higher educated, more likely to be smokers, and users of hormone replacement therapy, and have higher BMI. When stratified by histological subtypes, among the 1,374 EOC cases, 962 (70 %)
In this population-based case–control study, we observed a significant association between APOBEC3 deletion polymorphism and EOC risk. The association was similar when stratified by age, education, body mass index, hormone Table 1 Distribution of demographic characteristics for EOC cases and controls Category
Cases (N=1,374)
Controls (N=1,564)
P value
Age (year) Education (less than middle school) Ever smoker Use of hormone replacement therapy Body mass index (kg/m2) Histopathology Serous Mucinous Clear cell Endometrioid
50.6±7.6 538 (39.1 %)
50.3±7.0 578 (37.0 %)
0.431 0.386
204 (14.9 %) 56 (4.03 %)
224 (14.3 %) 44 (2.76 %)
0.776 0.183
23.8±3.5
23.6±3.4
0.267
Others
962 (70 %) 110 (8 %) 54 (4 %) 138 (10 %) 110 (8 %)
Continuous variables, mean values±standard deviation, P value from t tests; categorical variables, numbers and percentages, P values from x2 test
Tumor Biol. Table 2 Association between the APOBEC3 gene deletion and EOC risk a
Adjusted for age
b Adjusted for age, education, body mass index, hormone replacement therapy, and ever smoking
Genotypes Per copy deletion No deletion One copy deletion Two copy deletion Ptrend
No. of cases
No. of controls
1,374 1,010 342 22
1,564 1,254 300 10
replacement therapy, ever smoking, and histological subtypes. To the best of our knowledge, this should be the first study aiming to explore the association between CNVs of APOBEC3 gene and ovarian cancer risk. This provides evidence to implicate APOBEC3 gene deletion as a novel susceptibility factor for EOC risk. The APOBEC3 gene family, including APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3E, APOBEC3F, APOBEC3G, and APOBEC3H, plays pivotal roles in intracellular defense against viral infection [16, 17]. The APOBEC3 family of DNA-editing enzymes is thought to be part of the innate immune system by restricting retroviruses, mobile genetic elements like retro-transposons and endogenous retroviruses [18]. APOBEC3A gene, a member of the cytidine deaminase gene family, is located at 22q13.1q13.2. APOBEC3A exhibits antiviral activity against adenoassociated virus (AAV) and human T cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons [19]. The APOBEC3A gene could go towards explaining 5-methylcytidine mutation hotspots in cancer genomes [9]. APOBEC3B gene, which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and deaminase-independent mechanisms, is also located at 22q13.1-q13.2. Burns et al. identified APOBEC3B-catalyzed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumors evolve rapidly and manifest heterogeneity [20]; Very recently, Burns et al. screened 19 different cancer types by analyzing gene expression data and mutation patterns, distributions, and loads, and identified that its preferred target sequence is frequently mutated and clustered in at least six distinct cancers: bladder, cervix, lung (adenocarcinoma and squamous cell carcinoma), head and neck, and breast [14]; APOBEC3B were also confirmed to have a potential role in serous ovarian cancer genomic instability [21]. In current study, The APOBEC3 deletion, which is located between exon 5 of APOBEC3A gene and exon 8 of APOBEC3B gene and 29.5 kb in length, was explored for the possibility of being responsible for EOC risk among 1,374 EOC cases and 1,564 healthy controls. We first identified APOBEC3 gene deletion was significantly associated with increased EOC risk. As we know, CNVs can directly influence gene expression and phenotypic variation, disrupt gene
OR (95 % CI)a
OR (95 % CI)b
1.43 (1.15–1.79) 1.00 (reference) 1.46 (1.14–1.86) 2.53 (0.91–7.06) 1.50×10−3
1.44 (1.10–1.89) 1.00 (reference) 1.46 (1.13–1.87) 2.52 (0.93–6.87) 8.84×10−3
structure, alter gene dosage, and indirectly regulate gene function through position effects. Thus, the deletion in APOBEC3 gene may be a new biomarker for predicting EOC risk. Some limitations should be addressed in this study. First, as hospital-based case–control studies, the selection bias is unavoidable; since this study was restricted to a Chinese Han population, it is uncertain whether our findings can be replicated by other ethnic groups; and the statistical power of this study to perform interaction analyses between this deletion and known ovarian cancer risk factors is still limited. Further replication analyses and functional research may elucidate the finding that the CNV has significant association with EOC risk. In summary, this study found that the loss genotypes of APOBEC3 deletion were associated with an increased EOC risk in Chinese. The results suggest that the APOBEC3 deletion may be a new biomarker for EOC susceptibility. Validations with larger population-based studies in different ethnic groups, further research into the function of APOBEC3 deletion and its potential biological mechanism association may be warranted. Acknowledgments We thank all the staffs who were involved in the subject recruitment, telephone interviews, sample preparation, and laboratory assays for their hard works. Conflicts of interest None
References 1. Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Cl Ob. 2006;20:207–25. 2. Jemal A, Siegel R, Xu JQ, Ward E. Cancer statistics, 2010. CaCancer J Clin. 2010;60:277–300. 3. Holschneider CH, Berek JS. Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg Oncol. 2000;19:3–10. 4. Kurman RJ, Shih Ie M. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34:433–43. 5. Zheng W, Danforth KN, Tworoger SS, Goodman MT, Arslan AA, Patel AV, et al. Circulating 25-hydroxyvitamin d and risk of epithelial ovarian cancer: cohort consortium vitamin d pooling project of rarer cancers. Am J Epidemiol. 2010;172:70–80. 6. McLaughlin JR, Risch HA, Lubinski J, Moller P, Ghadirian P, Lynch H, et al. Reproductive risk factors for ovarian cancer in carriers of brca1 or brca2 mutations: a case–control study. Lancet Oncol. 2007;8:26–34.
Tumor Biol. 7. Shu XO, Dorjgochoo T, Li HL, Qian HZ, Yang G, Cai H, et al. Use of oral contraceptives, intrauterine devices and tubal sterilization and cancer risk in a large prospective study, from 1996 to 2006. Int J Cancer. 2009;124:2442–9. 8. Ma X, Beeghly-Fadiel A, Shu XO, Li H, Yang G, Gao YT, et al. Anthropometric measures and epithelial ovarian cancer risk among chinese women: results from the shanghai women’s health study. Br J Cancer. 2013;109:751–5. 9. Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet. 2010;11:446–50. 10. Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010;61:437–55. 11. Long J, Delahanty RJ, Li G, Gao YT, Lu W, Cai Q, et al. A common deletion in the apobec3 genes and breast cancer risk. J Natl Cancer Inst. 2013;105:573–9. 12. Xuan D, Li GL, Cai QY, Deming-Halverson S, Shrubsole MJ, Shu XO, et al. Apobec3 deletion polymorphism is associated with breast cancer risk among women of european ancestry. Carcinogenesis. 2013;34:2240–3. 13. Kuong KJ, Loeb LA. Apobec3b mutagenesis in cancer. Nat Genet. 2013;45:964–5. 14. Burns MB, Temiz NA, Harris RS. Evidence for apobec3b mutagenesis in multiple human cancers. Nat Genet. 2013;45:977–83. 15. Zhang T, Cai J, Chang J, Yu D, Wu C, Yan T, et al. Evidence of associations of apobec3b gene deletion with susceptibility to
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17.
18.
19.
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