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1.
PLoS One ; 14(8): e0221972, 2019.
Article in English | MEDLINE | ID: mdl-31469872

ABSTRACT

BACKGROUND: In Fetal Growth Restriction 'fetal programming' may take place via DNA methylation, which has implications for short-term and long-term health outcomes. Small-for-gestational age fetuses are considered fetal growth restricted, characterized by brain-sparing when fetal Doppler hemodynamics are abnormal, expressed as a cerebroplacental ratio (CPR) <1. We aimed to determine whether brain-sparing is associated with altered DNA methylation of selected genes. METHODS: We compared DNA methylation of six genes in 41 small-for-gestational age placentas with a normal or abnormal CPR. We selected EPO, HIF1A, VEGFA, LEP, PHLDA2, and DHCR24 for their role in angiogenesis, immunomodulation, and placental and fetal growth. DNA methylation was analyzed by pyrosequencing. RESULTS: Growth restricted fetuses with an abnormal CPR showed hypermethylation of the VEGFA gene at one CpG (VEGFA-309, p = .001) and an overall hypomethylation of the LEP gene, being significant at two CpGs (LEP-123, p = .049; LEP-51, p = .020). No differences in methylation were observed for the other genes. CONCLUSIONS: VEGFA and LEP genes are differentially methylated in placentas of small-for-gestational age fetuses with brain-sparing. Hypermethylation of VEGFA-309 in abnormal CPR-placentas could indicate successful compensatory mechanisms. Methylation of LEP-51 is known to suppress LEP expression. Hypomethylation in small-for-gestational age placentas with abnormal CPR may result in hyperleptinemia and predispose to leptin-resistance later in life.


Subject(s)
DNA Methylation , Leptin/genetics , Placenta/metabolism , Vascular Endothelial Growth Factor A/genetics , Adult , Alleles , CpG Islands , Epigenesis, Genetic , Female , Gene Expression Regulation , Gestational Age , Humans , Infant, Small for Gestational Age , Pregnancy , Ultrasonography, Prenatal , Young Adult
2.
Arterioscler Thromb Vasc Biol ; 37(6): 1168-1179, 2017 06.
Article in English | MEDLINE | ID: mdl-28408374

ABSTRACT

OBJECTIVE: Biglycan (BGN) has reduced expression in placentae from pregnancies complicated by fetal growth restriction (FGR). We used first trimester placental samples from pregnancies with later small for gestational age (SGA) infants as a surrogate for FGR. The functional consequences of reduced BGN and the downstream targets of BGN were determined. Furthermore, the expression of targets was validated in primary placental endothelial cells isolated from FGR or control pregnancies. APPROACH AND RESULTS: BGN expression was determined using real-time polymerase chain reaction in placental tissues collected during chorionic villous sampling performed at 10 to 12 weeks' gestation from pregnancies that had known clinical outcomes, including SGA. Short-interference RNA reduced BGN expression in telomerase-immortalized microvascular endothelial cells, and the effect on proliferation, angiogenesis, and thrombin generation was determined. An angiogenesis array identified downstream targets of BGN, and their expression in control and FGR primary placental endothelial cells was validated using real-time polymerase chain reaction. Reduced BGN expression was observed in SGA placental tissues. BGN reduction decreased network formation of telomerase-immortalized microvascular endothelial cells but did not affect thrombin generation or cellular proliferation. The array identified target genes, which were further validated: angiopoetin 4 (ANGPT4), platelet-derived growth factor receptor α (PDGFRA), tumor necrosis factor superfamily member 15 (TNFSF15), angiogenin (ANG), serpin family C member 1 (SERPIN1), angiopoietin 2 (ANGPT2), and CXC motif chemokine 12 (CXCL12) in telomerase-immortalized microvascular endothelial cells and primary placental endothelial cells obtained from control and FGR pregnancies. CONCLUSIONS: This study reports a temporal relationship between altered placental BGN expression and subsequent development of SGA. Reduction of BGN in vascular endothelial cells leads to disrupted network formation and alterations in the expression of genes involved in angiogenesis. Therefore, differential expression of these may contribute to aberrant angiogenesis in SGA pregnancies.


Subject(s)
Biglycan/metabolism , Chorionic Villi/blood supply , Chorionic Villi/metabolism , Endothelial Cells/metabolism , Fetal Growth Retardation/metabolism , Microvessels/metabolism , Neovascularization, Physiologic , Pregnancy Trimester, First/metabolism , Telomerase/metabolism , Animals , Biglycan/genetics , Case-Control Studies , Cell Line , Chorionic Villi Sampling , Female , Fetal Growth Retardation/genetics , Fetal Growth Retardation/physiopathology , Gene Expression Profiling , Gene Expression Regulation, Developmental , Humans , Infant, Newborn , Infant, Small for Gestational Age , Male , Mice, Inbred C57BL , Neovascularization, Physiologic/genetics , Pregnancy , Pregnancy Trimester, First/genetics , RNA Interference , Signal Transduction , Telomerase/genetics , Thrombin/metabolism , Time Factors , Tissue Culture Techniques , Transfection
3.
Biol Reprod ; 94(2): 37, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26740591

ABSTRACT

Variations in DNA methylation levels in the placenta are thought to influence gene expression and are associated with complications of pregnancy, like fetal growth restriction (FGR). The most important cause for FGR is placental dysfunction. Here, we examined whether changes in DNA methylation, followed by gene expression changes, are mechanistically involved in the etiology of FGR. In this retrospective case-control study, we examined the association between small-for-gestational-age (SGA) children and both DNA methylation and gene expression levels of the genes WNT2, IGF2/H19, SERPINA3, HERVWE1, and PPARG in first-trimester placental tissue. We also examined the repetitive element LINE-1. These candidate genes have been reported in the literature to be associated with SGA. We used first-trimester placental tissue from chorionic villus biopsies. A total of 35 SGA children (with a birth weight below the 10th percentile) were matched to 70 controls based on their gestational age. DNA methylation levels were analyzed by pyrosequencing and mRNA levels were analyzed by real-time PCR. None of the average DNA methylation levels, measured for each gene, showed a significant difference between SGA placental tissue compared to control tissue. However, hypermethylation of WNT2 was detected on two CpG positions in SGA. This was not associated with changes in gene expression. Apart from two CpG positions of the WNT2 gene, in early placenta samples, no evident changes in DNA methylation or expression were found. This indicates that the already reported changes in term placenta are not present in the early placenta, and therefore must arise after the first trimester.


Subject(s)
DNA Methylation , Fetal Growth Retardation/metabolism , Placenta/metabolism , Pregnancy Trimester, First/metabolism , Case-Control Studies , Female , Fetal Growth Retardation/genetics , Humans , Infant, Newborn , Infant, Small for Gestational Age , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , Pregnancy , Pregnancy Trimester, First/genetics , Retrospective Studies , Serpins/genetics , Serpins/metabolism , Wnt2 Protein/genetics , Wnt2 Protein/metabolism
4.
Epigenetics ; 7(11): 1268-78, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23018867

ABSTRACT

Epigenetic modifications, such as aberrant DNA promoter methylation, are frequently observed in cervical cancer. Identification of hypermethylated regions allowing discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3), or worse, may improve current cervical cancer population-based screening programs. In this study, the DNA methylome of high-grade CIN lesions was studied using genome-wide DNA methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methylated DNA Immunoprecipitation (MeDIP) combined with DNA microarray was used to compare DNA methylation profiles of epithelial cells derived from high-grade CIN lesions with normal cervical epithelium. Hypermethylated differentially methylated regions (DMRs) were identified. Validation of nine selected DMRs using BSP and MSP in cervical tissue revealed methylation in 63.2-94.7% high-grade CIN and in 59.3-100% cervical carcinomas. QMSP for the two most significant high-grade CIN-specific methylation markers was conducted exploring test performance in a large series of cervical scrapings. Frequency and relative level of methylation were significantly different between normal and cancer samples. Clinical validation of both markers in cervical scrapings from patients with an abnormal cervical smear confirmed that frequency and relative level of methylation were related with increasing severity of the underlying CIN lesion and that ROC analysis was discriminative. These markers represent the COL25A1 and KATNAL2 and their observed increased methylation upon progression could intimate the regulatory role in carcinogenesis. In conclusion, our newly identified hypermethylated DMRs represent specific DNA methylation patterns in high-grade CIN lesions and are candidate biomarkers for early detection.


Subject(s)
Biomarkers, Tumor/genetics , DNA Methylation , Genome, Human , Uterine Cervical Dysplasia/genetics , Uterine Cervical Neoplasms/genetics , Adenosine Triphosphatases/genetics , Adenosine Triphosphatases/metabolism , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Katanin , Middle Aged , Non-Fibrillar Collagens/genetics , Non-Fibrillar Collagens/metabolism , Oligonucleotide Array Sequence Analysis , Sequence Analysis, DNA , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Dysplasia/diagnosis , Uterine Cervical Dysplasia/metabolism
5.
Int J Radiat Oncol Biol Phys ; 79(2): 325-34, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-21195874

ABSTRACT

The aim of this study was to systematically review the prognostic and predictive significance of cell biological markers in cervical cancer patients primarily treated with (chemo)radiation. A PubMed, Embase, and Cochrane literature search was performed. Studies describing a relation between a cell biological marker and survival in ≥50 cervical cancer patients primarily treated with (chemo)radiation were selected. Study quality was assessed, and studies with a quality score of 4 or lower were excluded. Cell biological markers were clustered on biological function, and the prognostic and predictive significance of these markers was described. In total, 42 studies concerning 82 cell biological markers were included in this systematic review. In addition to cyclooxygenase-2 (COX-2) and serum squamous cell carcinoma antigen (SCC-ag) levels, markers associated with poor prognosis were involved in epidermal growth factor receptor (EGFR) signaling (EGFR and C-erbB-2) and in angiogenesis and hypoxia (carbonic anhydrase 9 and hypoxia-inducible factor-1α). Epidermal growth factor receptor and C-erbB-2 were also associated with poor response to (chemo)radiation. In conclusion, EGFR signaling is associated with poor prognosis and response to therapy in cervical cancer patients primarily treated with (chemo)radiation, whereas markers involved in angiogenesis and hypoxia, COX-2, and serum SCC-ag levels are associated with a poor prognosis. Therefore, targeting these pathways in combination with chemoradiation may improve survival in advanced-stage cervical cancer patients.


Subject(s)
Biomarkers, Tumor/physiology , Uterine Cervical Neoplasms , Analysis of Variance , Antigens, Neoplasm/physiology , Apoptosis Regulatory Proteins/physiology , Carbonic Anhydrase IX , Carbonic Anhydrases/physiology , Cell Proliferation , Combined Modality Therapy/methods , Combined Modality Therapy/mortality , Cyclooxygenase 2/physiology , ErbB Receptors/physiology , Female , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Prognosis , Receptor, ErbB-2/physiology , Serpins/physiology , Treatment Outcome , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/radiotherapy
6.
Hum Pathol ; 41(12): 1735-41, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21078436

ABSTRACT

The objective of this study is to correlate the expression of epidermal growth factor receptor (EGFR) components with clinical behavior of early-stage cervical cancer. Tissue samples of 336 consecutive Federation of International Gynecologists and Obstetricians stage IB-IIA cervical cancer patients all treated primarily by radical surgery were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. As representatives for the EGFR pathway, expression of EGFR, pEGFR, PTEN, pAKT, and pERK was assessed by immunohistochemistry on tissue microarrays. Positive immunostaining was observed for EGFR in 32.1%, for pEGFR in 21.0%, for PTEN in 38.3%, for pAKT in 5.3%, and for pERK in 4.3% of tumor samples. Positive EGFR immunostaining was associated with squamous cell carcinoma of the cervix (odds ratio [OR], 7.41; 95% confidence interval [CI], 3.38-16.23, P < .001), negative pEGFR immunostaining with poor differentiation (OR, 0.39; 95% CI, 0.20-0.73, P = .004), and negative PTEN immunostaining with metastatic pelvic lymph nodes (OR, 0.51; 95% CI, 0.30-0.90, P = .019). In multivariate analysis, only pelvic lymph node metastasis (hazard ratio, 6.11; 95% CI, 3.46-10.77, P < .001) and poor differentiation (hazard ratio, 1.91; 95% CI, 1.12-3.26, P = .018) were related to disease-specific survival. In early-stage cervical cancer, loss of PTEN expression is associated with pelvic lymph node metastasis, suggesting PTEN to be one of the tumor suppressor genes affecting pelvic lymph node metastasis. However, expression of EGFR pathway components does not appear to have prognostic impact in surgically treated early-stage cervical cancer.


Subject(s)
Carcinoma, Squamous Cell/metabolism , ErbB Receptors/metabolism , Lymph Nodes/pathology , Uterine Cervical Neoplasms/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/secondary , Cervix Uteri/metabolism , Cervix Uteri/pathology , Cervix Uteri/surgery , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Lymphatic Metastasis , Middle Aged , Netherlands/epidemiology , Odds Ratio , PTEN Phosphohydrolase/metabolism , Pelvis , Phosphorylation , Prognosis , Proto-Oncogene Proteins c-akt/metabolism , Survival Rate , Tissue Array Analysis , Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/pathology , Young Adult
7.
Cell Oncol ; 32(1-2): 131-43, 2010.
Article in English | MEDLINE | ID: mdl-20208141

ABSTRACT

OBJECTIVES: To determine methylation status of nine genes, previously described to be frequently methylated in cervical cancer, in squamous intraepithelial lesions (SIL). METHODS: QMSP was performed in normal cervix, low-grade (L)SIL, high-grade (H)SIL, adenocarcinomas and squamous cell cervical cancers, and in corresponding cervical scrapings. RESULTS: Only CCNA1 was never methylated in normal cervices and rarely in LSILs. All other genes showed methylation in normal cervices, with CALCA, SPARC and RAR-beta(2) at high levels. Methylation frequency of 6 genes (DAPK, APC, TFPI2, SPARC, CCNA1 and CADM1) increased with severity of the underlying cervical lesion. DAPK showed the highest increase in methylation frequency between LSIL and HSIL (10% vs. 40%, p<0.05), while CCNA1 and TFPI2 were most prominently methylated in cervical cancers compared to HSILs (25% vs. 52%, p<0.05, 30% vs. 58%, p<0.05). CADM1 methylation in cervical cancers was related to depth of invasion (p<0.05) and lymph vascular space involvement (p<0.01), suggesting a role in invasive potential of cervical cancers. Methylation ratios in scrapings reflected methylation status of the underlying lesions (p<0.05). CONCLUSION: Methylation of previously reported cervical cancer specific genes frequently occurs in normal epithelium. However, frequency of methylation increases during cervical carcinogenesis, with CCNA1 and DAPK as the best markers to distinguish normal/LSIL from HSIL/cancer lesions.


Subject(s)
Biomarkers, Tumor/genetics , DNA Methylation , Promoter Regions, Genetic , Uterine Cervical Dysplasia/genetics , Female , Humans , Middle Aged , Neoplastic Processes , Uterine Cervical Dysplasia/pathology
8.
Clin Cancer Res ; 15(23): 7389-97, 2009 Dec 01.
Article in English | MEDLINE | ID: mdl-19920104

ABSTRACT

PURPOSE: Activation of the epidermal growth factor receptor (EGFR) signaling pathway has been reported to induce resistance to (chemo)radiation in cancers, such as head and neck cancer, whereas EGFR-targeted agents in combination with (chemo)radiation seem to improve treatment efficacy. The aim of this study was to determine the relation between proteins involved in the EGFR pathway and response to (chemo)radiation and survival in a large, well-documented series of cervical cancer patients. EXPERIMENTAL DESIGN: Pretreatment tissue samples of 375 consecutive International Federation of Gynecologists and Obstetricians stage Ib to IVa cervical cancer patients treated with (chemo)radiation between January 1980 and December 2006 were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. Protein expression of EGFR, phosphorylated EGFR (pEGFR), PTEN, phosphorylated AKT, and phosphorylated extracellular signal-regulated kinase (pERK) was assessed by immunohistochemistry on tissue microarrays. RESULTS: EGFR staining was present in 35.3%, pEGFR in 19.7%, PTEN in 34.1%, phosphorylated AKT in 4.1%, and pERK in 29.2% of tumors. pEGFR staining was related to PTEN (P = 0.001) and pERK staining (P = 0.004). EGFR staining was inversely related to PTEN (P = 0.011). In multivariate analysis, membranous staining of EGFR [hazard ratio (HR), 1.84; 95% confidence interval (95% CI), 1.20-2.82; P = 0.005] and cytoplasmic staining of pEGFR (HR, 1.71; 95% CI, 1.11-2.66; P = 0.016) were independent predictors of poor response to (chemo)radiation. Membranous EGFR staining also was an independent prognostic factor for poor disease-specific survival (HR, 1.54; 95% CI, 1.09-2.17; P = 0.014). CONCLUSIONS: EGFR and pEGFR immunostainings are frequently observed and independently associated with poor response to therapy and disease-specific survival in cervical cancer patients primarily treated by (chemo)radiation. Our data present the EGFR pathway as a promising therapeutic target in already ongoing clinical trials.


Subject(s)
ErbB Receptors/biosynthesis , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Biopsy , Brachytherapy/methods , Female , Humans , Hysterectomy , Immunohistochemistry/methods , Middle Aged , Phosphorylation , Prospective Studies , Protein Array Analysis , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Treatment Outcome , Uterine Cervical Neoplasms/mortality
9.
Cancer Epidemiol Biomarkers Prev ; 18(11): 3000-7, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19843677

ABSTRACT

PURPOSE: Recently, we reported 13 possible cervical cancer-specific methylated biomarkers identified by pharmacologic unmasking microarray in combination with large-genome computational screening. The aim of the present study was to perform an in-depth analysis of the methylation patterns of these 13 candidate genes in cervical neoplasia and to determine their diagnostic relevance. EXPERIMENTAL DESIGN AND RESULTS: Five of the 13 gene promoters (C13ORF18, CCNA1, TFPI2, C1ORF166, and NPTX1) were found to be more frequently methylated in frozen cervical cancer compared with normal cervix specimens. Quantitative methylation analysis for these five markers revealed that both CCNA1 and C13ORF18 were methylated in 68 of 97 cervical scrapings from cervical cancer patients and in only 5 and 3 scrapings, respectively, from 103 healthy controls (P < 0.0005). In cervical scrapings from patients referred with an abnormal Pap smear, CCNA1 and C13ORF18 were methylated in 2 of 43 and 0 of 43 CIN 0 (no cervical intraepithelial neoplasia) and in 1 of 41 and 0 of 41 CIN I, respectively. Furthermore, 8 of 43 CIN II, 22 of 43 CIN III, and 3 of 3 microinvasive cancer patients were positive for both markers. Although sensitivity for CIN II or higher (for both markers 37%) was low, specificity (96% and 100%, respectively) and positive predictive value (92% and 100%, respectively) were high. CONCLUSION: Methylation of CCNA1 and C13ORF18 in cervical scrapings is strongly associated with CIN II or higher-grade lesions. Therefore, these markers might be used for direct referral to gynecologists for patients with a methylation-positive scraping.


Subject(s)
Biomarkers, Tumor/genetics , Cervix Uteri/pathology , Cyclin A1/genetics , DNA Methylation , Transcription Factors/genetics , Uterine Cervical Dysplasia/genetics , Uterine Cervical Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Case-Control Studies , DNA, Viral/analysis , DNA, Viral/genetics , Female , Humans , Middle Aged , Neoplasm Invasiveness , Papanicolaou Test , Polymerase Chain Reaction , Prognosis , Sensitivity and Specificity , Uterine Cervical Neoplasms/pathology , Vaginal Smears , Uterine Cervical Dysplasia/pathology
10.
Ned Tijdschr Geneeskd ; 153: A628, 2009.
Article in Dutch | MEDLINE | ID: mdl-19785834

ABSTRACT

The publication of a practice guideline for primary and secondary prevention of cervical cancer by the Dutch College of General Practitioners was appropriate since the vaccination against two high-risk human papillomaviruses (hr-HPV 16 and 18) was recently included in the National Immunization Programme of the Netherlands. Despite vaccination, population-based screening for cervical neoplasia needs to be continued. Moreover, it will take over a decade before vaccination will affect the prevalence of cervical neoplasia. Short term improvement of prevention of cervical neoplasia should therefore focus on screening technology and strategy. Molecular tests based on detection of hr-HPV or DNA changes occurring early in cervical carcinogenesis might improve the efficacy of the screening, which in the Netherlands is currently done by Pap smear. In addition, the high number of women not responding on an invitation for screening might be reduced by a self-sampling approach.


Subject(s)
Papillomavirus Infections/diagnosis , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/administration & dosage , Practice Guidelines as Topic , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/prevention & control , Female , Humans , Mass Screening , Molecular Diagnostic Techniques , Netherlands , Papanicolaou Test , Papillomavirus Infections/epidemiology , Prevalence , Uterine Cervical Neoplasms/epidemiology , Vaginal Smears
11.
Int J Radiat Oncol Biol Phys ; 75(1): 203-11, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19695437

ABSTRACT

PURPOSE: Preclinical data indicate a synergistic effect on apoptosis between irradiation and recombinant human (rh) tumor necrosis factor-related apoptosis inducing ligand (TRAIL), making the TRAIL death receptors (DR) interesting drug targets. The aim of our study was to analyze the expression of DR4, DR5, and TRAIL in cervical cancer and to determine their predictive and prognostic value. METHODS AND MATERIALS: Tissue microarrays were constructed from tumors of 645 cervical cancer patients treated with surgery and/or (chemo-)radiation between 1980 and 2004. DR4, DR5, and TRAIL expression in the tumor was studied by immunohistochemistry and correlated to clinicopathological variables, response to radiotherapy, and disease-specific survival. RESULTS: Cytoplasmatic DR4, DR5, and TRAIL immunostaining were observed in cervical tumors from 99%, 88%, and 81% of the patients, respectively. In patients treated primarily with radiotherapy, TRAIL-positive tumors less frequently obtained a pathological complete response than TRAIL-negative tumors (66.3% vs. 79.0 %; in multivariate analysis: odds ratio: 2.09, p

Subject(s)
Cytoplasm/chemistry , Neoplasm Proteins/analysis , Receptors, TNF-Related Apoptosis-Inducing Ligand/analysis , TNF-Related Apoptosis-Inducing Ligand/analysis , Uterine Cervical Neoplasms/chemistry , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis , Carboplatin/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Immunohistochemistry , Middle Aged , Multivariate Analysis , Prognosis , Radiotherapy Dosage , Tissue Array Analysis , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/radiotherapy , Young Adult
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