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Polymorphisms in the SULF1 Gene Are Associated with Early Age of Onset and Survival of Ovarian Cancer Chan Han, Emory University Yu-Jing Huang, M

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Polymorphisms in the SULF1 Gene Are Associated with Early Age of Onset and Survival of Ovarian Cancer Chan Han, Emory University Yu-Jing Huang, M Polymorphisms in the SULF1 gene are associated with early age of onset and survival of ovarian cancer Chan Han, Emory University Yu-Jing Huang, M. D. Anderson Cancer Center Karen H Lu, M. D. Anderson Cancer Center Zhensheng Liu, M. D. Anderson Cancer Center Gordon B Mills, M. D. Anderson Cancer Center Qingyi Wei, M. D. Anderson Cancer Center Li-E Wang, M. D. Anderson Cancer Center Journal Title: Journal of Experimental and Clinical Cancer Research Volume: Volume 30, Number 1 Publisher: BioMed Central | 2011-01-07, Pages 5-5 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1186/1756-9966-30-5 Permanent URL: https://pid.emory.edu/ark:/25593/rg4xv Final published version: http://dx.doi.org/10.1186/1756-9966-30-5 Copyright information: © 2011 Han et al. licensee BioMed Central Ltd. This is an Open Access work distributed under the terms of the Creative Commons Attribution 2.0 Generic License (http://creativecommons.org/licenses/by/2.0/). Accessed September 29, 2021 4:50 AM EDT Han et al. Journal of Experimental & Clinical Cancer Research 2011, 30:5 http://www.jeccr.com/content/30/1/5 RESEARCH Open Access Polymorphisms in the SULF1 gene are associated with early age of onset and survival of ovarian cancer Chan H Han1, Yu-Jing Huang1, Karen H Lu2, Zhensheng Liu1, Gordon B Mills3, Qingyi Wei1, Li-E Wang1* Abstract Background: SULF1 (sulfatase 1) selectively removes the 6-O-sulphate group from heparan sulfate, changing the binding sites for extracellular growth factors. SULF1 expression has been reported to be decreased in various cancers, including ovarian cancer. We hypothesized that single nucleotide polymorphisms (SNPs) of SULF1 would impact clinicopathologic characteristics. Methods: We genotyped five common (minor allele frequency>0.05) regulatory SNPs with predicted functionalities (rs2623047 G>A, rs13264163 A>G, rs6990375 G>A, rs3802278 G>A, and rs3087714 C>T) in 168 patients with primary epithelial ovarian cancer, using the polymerase chain reaction-restriction fragment length polymorphism method. Results: We found that rs2623047 G>A was significantly associated with an early age of onset of ovarian cancer in the G allele dose-response manner (P = 0.027; Ptrend = 0.007) and that rs2623047 GG/GA genotypes were associated with longer progression-free survival; rs6990375 G>A was also associated with the early age of onset in the A allele dose-response manner (P = 0.013; Ptrend= 0.009). The significant differences in age of disease onset persisted among carriers of haplotypes of rs2623047 and rs6990375 (P = 0.014; Ptrend = 0.004). In luciferase reporter gene assays, rs2623047 G allele showed a slightly higher promoter activity than the A allele in the SKOV3 tumorigenic cell line. Conclusions: These findings suggest that genetic variations in SULF1 may play a role in ovarian cancer onset and prognosis. Further studies with large sample sizes and of the mechanistic relevance of SULF1 SNPs are warranted. Background with numerous mediators including growth factors, cyto- SULF1 is a newly identified human sulfatase with kines, chemokines, and adhesion molecules, HSGAGs are aryl-sulfatase activities, which can influence the sulfation involved in a wide array of biological processes, such as status and biological function of heparan sulfate proteo- homeostasis, anticoagulation, angiogenesis, embryogen- glycans (HSPGs) [1]. This heparan sulfate 6-O-endosulfa- esis, as well as in oncogenic transformation of normal tase selectively removes 6-O-sulphate group and alters cells to tumor cells [5-10]. the binding sites of signaling molecules [2]. HSPGs are The correlation between SULF1 and cancer risk has protein-conjugated forms of heparin sulfate glycosamino- mainly been studied in terms of gene expression. SULF1 glycans (HSGAGs) in vivo and major constituents of the expression is decreased in multiple malignant lineages, extracellular matrix (ECM).HSGAGsintheECMinter- and its re-expression is known to be associated with act with many signaling molecules, regulate their biologi- decreased signaling of heparin-binding growth factors, cal activities, and express profound effects on cell growth cell proliferation, and the invasiveness of cancer cells kinetics and metastasis of tumor cells [3,4]. By interacting [11-14]. In ovarian cancer, decreased expression of SULF1 and its correlation with decreased sensitivity to * Correspondence: [email protected] cisplatin (a standard chemotherapeutic agent) were also 1 Department of Epidemiology, The University of Texas M. D. Anderson reported [12,15]. Cancer Center, Houston, TX 77030, USA Full list of author information is available at the end of the article © 2011 Han et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Han et al. Journal of Experimental & Clinical Cancer Research 2011, 30:5 Page 2 of 7 http://www.jeccr.com/content/30/1/5 Loss of heterozygosity or hypermethylation of the pro- SNP Selection and Genotyping moter region has been suggested as potential mechan- Using SULF1 gene position from International HapMap isms for SULF1 down-regulation in ovarian cancer [14]. project http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/ Besides, genetic variation has been implicated in altered hapmap28_B36/#search with the extension of 2 kb at both gene expression, especially those regulatory polymorph- sides to cover near gene regions (chr8:70539427.. isms that are located in promoter regions [16,17]. How- 70737701), we found that five of 355 SNPs were common ever, genetic variation in SULF1 has not been explored in HapMap Caucasian population with one of following in ovarian cancer. In this study, we genotyped five com- predicted functionalities at the SNP Function Prediction mon (i.e. minor allele frequency>0.05) single nucleotide website http://snpinfo.niehs.nih.gov/snpfunc.htm: (1) polymorphisms (SNPs) with predicted functionalities affecting transcription factor binding sites (TFBS) activity (rs2623047 G>A, rs13264163 A>G, rs6990375 G>A, in the putative promoter region, (2) affecting splicing rs3802278 G>A, and rs3087714 C>T ) to evaluate asso- activity, or (3) affecting the microRNA binding sites activ- ciations between these potentially functional SULF1 ity. Therefore, we genotyped all of these five SNPs: SNPs and clinical outcomes in 168 ovarian cancer rs2623047 G>A, rs13264163 A>G, rs6990375 G>A, patients whose DNA and clinic variables were available, rs3802278 G>A, and rs3087714 C>T. and investigated whether the promoter activity of The genotyping was performed by the polymerase rs2623047 A>G may be underlying the functional chain reaction-restriction fragment length polymorphism significance. method (PCR-RFLP) using genomic DNA. Table 1 shows the primers and PCR information for each SNP. The Methods PCR conditions consisted of an initial melting step of 95° Study Population C for 5 min, followed by 35 cycles of denaturation (95 °C The study population and data collection were described for 30 seconds), annealing (52 - 55 °C for 45 sec accord- previously [18]. Briefly, the 168 patients were registered ing to SNPs), and extension (72°C for 1 min), and a final at The University of Texas M. D. Anderson Cancer extension step of 72°C for 10 min. The digested products Center between 2000 and 2007 and diagnosed with his- were checked on a 3% MetaPhor agarose gel containing topathologically confirmed primary epithelial ovarian ethidium bromide. The gene structure, SNP location, pre- cancer. Patients had been treated with chemotherapy, a dicted functionality of SNPs, and electrophoresis gel pic- combination of platinum (carboplatin, cisplatin) and tax- tures are shown in Figure 1A. The genotypes were anes (taxol, docetaxel) following optimal debulking or double-checked by two people for quality control, and cyto-reductive surgery. Available demographic character- any uncertain results were repeated to reach a 100% con- istics included age at diagnosis and race, and clinico- cordance. Genotyping of 10% of samples were randomly pathologic characteristics including tumor stage, cell performed twice, and no discrepancy was observed. type and grade, optimality of the primary debulking operation, chemotherapy regimen, number of che- Construction of Reporter Plasmids motherapies, disease recurrence, and response of tumors Reporter constructs were prepared for rs2623047 G>A to chemotherapy. The optimal debulking or cyto-reduc- by amplifying 1803 bp of the SULF1 promoter region tive surgery is defined as the largest residual tumor (from -1784 to +18 relative to the transcription start nodule measuring 1 cm or less, according to the Gyneco- site) with either rs2623047 G or A allele by using a pair logic Oncology Group [19]. The response evaluation of primers 5’-AAGAGCTCTTGGGAATGCCTCATA- criteria in solid tumors (RECIST) [20] were used to GACAG-3’ (forward) and 5’-AAGCTAGCGGTCTGA- define the response of tumors to treatment. GAACTCCCAGTCAA-3’ (reverse). SacI and NheI Overall survival (OS) and progression-free survival restriction enzymes (New England BioLabs, Beverly, (PFS) were calculated as the date of disease diagnosis to MA) were used to cleave the amplicons, and the pGL4 the date of death or last contact or the date of recur- vector (Promega, Madison, WI) and T4 DNA ligase rence or progression, accordingly. Disease recurrence (New England BioLabs) were used for ligation. was defined as the reappearance of any lesion that had previously disappeared or the appearance of a new Transient Transfection and Luciferase Reporter Gene lesion that was histopathologically confirmed by a Assay biopsy. Information about the date of last contact and The ovarian cancer cell lines OVCA429 and SKOV-3 status of patients at the last contact was obtained from were cultured in 1x McCoy’s 5A modified medium and the M. D. Anderson Tumor Registry and Social Security minimum essential medium, and the human cervical Death Index, when this information was missing from cancer cell line HeLa was cultured in Dulbecco’smodi- the medical records.
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