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ABSTRACT: There is no gene signature for predicting relapse and survival of cervical cancer with early stage currently. In this study, we investigate whether gene expression profiling of cervical cancer could be used to predict the prognosis of patient. A series of 100 primary cervical cancer patients who underwent radical hysterectomy between January 2001 and October 2006 were analyzed for gene expression profiles by using a custom oligonucleotide microarray containing probes for 1440 human tumor-related gene transcripts. Supervised analysis of gene expression data identified 19 genes that exhibited differential expression between cervical cancer and normal cervix. Then, all 100 patients were divided into the training (n = 50) and testing sets (n = 50). Using Cox regression and risk-score analysis, we identified a 7-gene (UBL3, FGF3, BMI1, PDGFRA, PTPRF, RFC4, and NOL7) signature for predicting relapse of patient in the training set. The 7-gene signature was validated by the testing set (sensitivity, 84.6%; specificity, 91.9%; positive predictive value, 78.6%; negative predictive value, 94.4%). Patients with high-risk 7-gene signature had poor relapse-free survivals (RFS) than patients with low-risk 7-gene signature in both training set (P = 0.026) and testing set (P = 0.042). Multivariate analysis showed that the FIGO stage and 7-gene signature are independent prognostic factors associated with RFS of cervical cancer patients. The 7-gene signature can predict cancer recurrence and survival of cervical cancer patients. This may have prognostic or therapeutic implications for the future management of cervical cancer patients.
Medical Oncology 01/2012; 29(4):2911-8. · 2.14 Impact Factor
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ABSTRACT: Small cell carcinoma of the cervix (SCCC) is very rare, and due to the long time period required to recruit sufficient numbers of patients, there is a paucity of information regarding the prognostic factors associated with survival. MicroRNAs (miRNAs) have been used as cancer-related biomarkers in a variety of tumor types, and the objective of this study was to determine whether microRNA expression profiles can predict clinical outcome in SCCC.
Forty-four patients with SCCC who underwent radical hysterectomy between January 2000 and October 2009 were enrolled. Using the GeneCopoeia All-in-One™ Customized Human qPCR Primer Array, the expression profiles of 30 miRNAs associated with tumor metastasis was obtained from the formalin-fixed paraffin embedded samples of all 44 patients. Seven miRNAs, has-let-7c, has-miR-10b, has-miR-100, has-miR-125b, has-miR-143, has-miR-145 and has-miR-199a-5p were significantly down-regulated in advanced stage SCCC patients (FIGO IB2-IV) compared to early stage SCCC patients (FIGOIB1). Among, downregulation of six miRNAs, has-let-7c, has-miR-100, has-miR-125b, has-miR-143, has-miR-145 and has-miR-199a-5p were significantly associated with lymph node metastasis and reduced survival in SCCC. Kaplan-Meier survival analyses revealed that SCCC patients with low expression of has-miR-100 (P = 0.019) and has-miR-125b (P = 0.020) projected a significant tendency towards poorer prognosis.
This study demonstrates that downregulation of 7 miRNA associated with advanced stage, 6 miRNAs with metastasis and 2 with poor prognosis in SCCC. Functional analysis of these miRNAs may enhance our understanding of SCCC, as altered expression of specific miRNAs may regulate the metastatic pathway and provide novel targets for therapy.
PLoS ONE 01/2012; 7(3):e33762. · 4.09 Impact Factor
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Guo-Liang Huang,
Bin-Kui Li,
Mei-Yin Zhang,
Rong-Rong Wei,
Yun-Fei Yuan,
Ming Shi,
Xiao-Qian Chen, Long Huang,
Hui-Zhong Zhang,
Wanqing Liu,
Bi-Jun Huang,
Honghua Li,
Xiao-Feng Zheng,
Xian-Rong Luo,
Hui-Yun Wang
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ABSTRACT: The role of heparanase (HPSE) gene in cancers including hepatocellular carcinoma (HCC) is currently controversial. This study was aimed at investigating the impact of genetic alteration and expression change of HPSE on the progression and prognosis of HCC.
THE HPSE GENE WAS STUDIED IN THREE DIFFERENT ASPECTS: (1) loss of heterozygosity (LOH) by a custom SNP microarray and DNA copy number by real-time PCR; (2) mRNA level by qRT-PCR; and (3) protein expression by immunohistochemistry. The clinical significances of allele loss and expression change of HPSE were analyzed.
Microarray analysis showed that the average LOH frequency for 10 SNPs located within HPSE gene was 31.6%, three of which were significantly correlated with tumor grade, serum HBV-DNA level, and AFP concentration. In agreement with SNP LOH data, DNA copy number loss of HPSE was observed in 38.74% (43/111) of HCC cases. HPSE mRNA level was notably reduced in 74.1% (83/112) of tumor tissues compared with non-tumor liver tissues, which was significantly associated with DNA copy number loss, increased tumor size, and post-operative metastasis. HPSE protein level was also remarkably reduced in 66.3% (53/80) of tumor tissues, which was correlated with tumor grade. Patients with lower expression level of HPSE mRNA or protein had a significantly lower survival rate than those with higher expression. Cox regression analysis suggested that HPSE protein was an independent predictor of overall survival in HCC patients.
The results in this study demonstrate that genetic alteration and reduction of HPSE expression are associated with tumor progression and poor prognosis of HCCs, suggesting that HPSE behaves like a tumor suppressor gene and is a potential prognostic marker for HCC patients.
PLoS ONE 01/2012; 7(8):e44061. · 4.09 Impact Factor
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Li He,
Hui Ding,
Jian-Hua Wang,
Yun Zhou,
Li Li,
Yan-Hong Yu, Long Huang,
Wei-Hua Jia,
Musheng Zeng,
Jing-Ping Yun,
Rong-Zhen Luo,
Min Zheng
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ABSTRACT: The aim of this study was to identify a biomarker useful in the diagnosis and therapy of ovarian malignant germ cell tumor (OMGCT).
The karyopherin 2 (KPNA2) expression in OMGCT and normal ovarian tissue was determined by standard gene microarray assays, and further validated by a quantitative RT-PCR and immunohistochemistry. The correlation between KPNA2 expression in OMGCT and certain clinicopathological features were analyzed. Expression of SALL4, a stem cell marker, was also examined in comparison with KPNA2.
KPNA2 was found to be over-expressed by approximately eight-fold in yolk sac tumors and immature teratomas compared to normal ovarian tissue by microarray assays. Overexpression was detected in yolk sac tumors, immature teratomas, dysgerminomas, embryonal carcinomas, mature teratomas with malignant transformation and mixed ovarian germ cell tumors at both the transcription and translation levels. A positive correlation between KPNA2 and SALL4 expression at both the transcription level (R = 0.5120, P = 0.0125), and the translation level (R = 0.6636, P<0.0001), was presented. Extensive expression of KPNA2 was positively associated with pathologic type, recurrence and uncontrolled, ascitic fluid presence, suboptimal cytoreductive surgery necessity, resistance/refraction to initial chemotherapy, HCG level and SALL4 level in OMGCT patients. KPNA2 was found to be an independent factor for 5-year disease-free survival (DFS) of OMGCT (P = 0.02). The 5-year overall survival (OS) and DFS rate for KPNA2-low expression patients (88% and 79%, n = 48) were significantly higher than the OS and DFS rate for KPNA2-high expression patients (69% and 57.1%, n = 42)(P = 0.0151, P = 0.0109, respectively). The 5-year OS and DFS rate for SALL4-low expression patients (84% and 74%, n = 62) was marginally significantly higher than the high expression patients (78.6% and 71.4%, n = 28)(P = 0.0519, P = 0.0647, respectively).
KPNA2 is a potential candidate molecular marker and important prognostic marker in OMGCT patients.
PLoS ONE 01/2012; 7(9):e42992. · 4.09 Impact Factor
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ABSTRACT: The aim of this study was to evaluate type II radical hysterectomy with or without adjuvant therapy as a treatment for patients with pelvic lymph node metastasis (PLNM) and stage IB-IIB cervical carcinoma.
A total of 288 patients with stage IB-IIB cervical carcinoma and confirmed PLNM who underwent a type II radical hysterectomy between 1995 and 2005 were retrospectively evaluated.
The 5-year overall survival (OS) rate for this cohort was 65.6%, and independent prognostic factors identified for PLNM patients included a non-squamous cell histological subtype and parametrial involvement. Survival differences between patients that received or did not receive adjuvant treatment were also evaluated, and the 5-year OS and DFS rates for patients who did not receive adjuvant therapy (47 and 41.4%, respectively) were much lower than the rates for patients who did receive adjuvant therapies (67.7 and 59.4%, respectively). However, these differences were not statistically significant (OS, P = 0.057; DFS, P = 0.080).
Type II radical hysterectomy, in combination with adjuvant therapies, is an efficient treatment for PLNM patients with stage IB-IIB cervical cancer.
Journal of Surgical Oncology 05/2011; 104(5):480-5. · 2.10 Impact Factor
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ABSTRACT: This retrospective study evaluated the feasibility and effectiveness of type II radical hysterectomies alone, or in combination with adjuvant treatment, for the treatment of patients with stage IB-IIB cervical cancer with or without high-risk factors.
A total of 960 stage IB-IIB patients who underwent type II radical hysterectomies between 1995 and 2004 were enrolled and retrospectively analyzed.
Uterine corpus invasion, parametrial margin involvement, and pelvic lymph node metastasis were identified as independent prognostic factors for stage IB patients. For stage IIA-IIB patients, histologic type, parametrial margin involvement, and pelvic lymph node metastasis were identified as independent prognostic factors. The 5-year overall survival (OS) rates for patients with stage IB versus stage IIA-IIB cervical carcinomas were 88.4% and 78.5%, respectively. Moreover, adjuvant radiotherapy and chemotherapy improved the 5-year OS rates of stage IIA-IIB patients associated with high-risk factors. The overall recurrence rate for this cohort was 14.4%.
Our findings show that type II radical hysterectomy is a feasible treatment option for stage IB-IIB cervical carcinoma patients. Furthermore, type II radical hysterectomy combined with adjuvant post-operative therapy improves the OS of women with high-risk factors for cervical carcinoma.
Journal of Surgical Oncology 04/2011; 103(5):435-41. · 2.10 Impact Factor
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ABSTRACT: Pelvic lymph node metastasis (PLNM) is an important prognostic factor for patients with cervical carcinoma. The objective of this study was to identify a gene-expression signature that could predict PLNM in cervical carcinoma.
Eighty-eight women with cervical carcinoma with PLNM (n = 23) and without PLNM (n = 65) were divided randomly into a training group and a test group. An oligonucleotide microarray that contained probes for 1440 human cancer-related genes was fabricated in-house and was used to detect the gene expression profile of cervical carcinoma. The gene expression levels detected in the microarray were verified by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR).
A gene-expression signature for predicting PLNM was developed in patients from the training group, including 11 genes: ribosomal protein L35 (RPL35); thymosin β 10 (TMSB10); tyrosine 3-mono-oxytenase/tryptophan 5-mono-oxygenase activation protein, ζ polypeptide (YWHAZ); biotinidase (BTD); lactate dehydrogenase A (LDHA); glucuronidase β (GUSB); superoxide dismutase 2 (SOD2); nuclear receptor subfamily 3, group C, member 2 (NR3C2); fructosamine 3 kinase (FN3K); x-ray repair cross-complementing 4 (XRCC4); and wingless-type mouse mammary tumor virus integration site family member 2 (WNT2). In the test group, the signature's accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 91%, 90.9%, 93.9%, 83.3%, and 96.9%, respectively, for predicting PLNM. The expression levels of 5 genes in the signature were confirmed by qRT-PCR. A multivariate analysis demonstrated that patients with 11-gene high-risk scores were had a 33-fold increased risk for PLNM compared with patients who had low-risk scores. The 5-year overall and disease-free survival rates for patients who had 11-gene high-risk scores were marginally significantly lower than the rates for patients who had 11-gene low-risk scores (P = .087 and P = .174, respectively).
In this study, 11-gene signature for predicting PLNM in cervical carcinoma was identified that may help clinicians in planning therapy for patients with cervical carcinoma.
Cancer 02/2011; 117(15):3363-73. · 4.77 Impact Factor
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ABSTRACT: To evaluate karyopherin 2 (KPNA2) as a biomarker for epithelial ovarian cancer.
A candidate oncogene, KPNA2, was identified in gene microarray assays of epithelial ovarian cancer tissues compared with normal human ovarian surface epithelial tissues. Differences in expression were further validated by real-time polymerase chain reaction and Western blotting. KPNA2 expression patterns in epithelial ovarian cancer tissues were determined using immunohistochemistry and were compared with specific clinicopathologic features of the patient specimens analyzed. Factors associated with patient survival were also statistically analyzed.
KPNA2 was found to be upregulated approximately eightfold in epithelial ovarian cancer tissues compared with human ovarian surface epithelial tissues, and overexpression was detected at the level of both transcription and translation. Immunohistochemical assays detected positive KPNA2 expression (++ or +++) in 50 of 102 (49.0%) epithelial ovarian cancer specimens, whereas negative KPNA2 expression (- or +) was observed in all of the human ovarian surface epithelial tissues analyzed. KPNA2 overexpression was also found to be significantly associated with specific histologic type, an advanced stage, a high histologic grade, and tumor recurrence (P<.05). The 5-year overall survival rate for KPNA2-negative compared with KPNA2-positive patients was 73.1% and 60.5%, respectively (P<.05).
KPNA2 may play an important role in the development, differentiation, and carcinogenesis of epithelial ovarian cancer and therefore could be an indicator of poor prognosis for patients with epithelial ovarian cancer.
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Obstetrics and Gynecology 10/2010; 116(4):884-91. · 4.73 Impact Factor
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ABSTRACT: Ovarian fibrosarcomas are very rare tumors, and therefore, few case studies have evaluated the prognostic factors of this disease. To our knowledge, this study represents the largest study to evaluate the clinical and pathologic factors associated with ovarian fibrosarcoma patients.
Thirty-one cases of ovarian fibrosarcoma were retrospectively reviewed, which included medical records for eight patients, and 23 published case reports from 1995 through 2009. Patient treatment regimens included total hysterectomy with bilateral adnexectomy and an omentectomy (BAO) (n = 9), oophorectomy (OR) (n = 8), chemotherapy (CT) (n = 1), BAO followed by chemotherapy (BAO+CT) (n = 11), BAO followed by radiotherapy (BAO+RT) (n = 1), and oophorectomy followed by radiotherapy (OR + RT) (n = 1).
The patients of this cohort were staged according to the guidelines of the Federation of Gynecology and Obstetrics (FIGO), with 15, 6, 9, and 1 stage I-IV cases identified, respectively. Mitotic count values were also evaluated from 10 high-power fields (HPFs), and 3 cases had an average mitotic count < 4, 18 cases were between 4 and 10, and 10 cases had an average mitotic count value ≥ 10. The Ki-67 (MIB-1) proliferation index values were grouped according to values that as follows: < 10% (n = 5), between 10% and 50% (n = 9), and ≥ 50% (n = 5). Positive expression of vimentin (100%, 22/22) and negative expression of CD117 (0%, 5/5) were also detected. Moreover, expression of smooth muscle actin (2/18), desmin (1/13), epithelial membrane antigen (0/11), S-100 (1/19), CD99 (0/6), CD34 (1/5), α-inhibin (7/15), estrogen receptor (1/6), and progesterone receptor (1/6) were reported for subsets of the cases examined. After a median follow-up period of 14 months (range, 2-120), the 2-year overall survival rates (OS) and disease-free survival (DFS) rates for all patients were 55.9% and 45.4%, respectively. Cox proportional hazard regression analysis of survival showed that FIGO stage (P = 0.007) and treatment (P = 0.008) were predictive of poor prognosis. Furthermore, patients with stage I tumors that received BAO+CT were associated with a better prognosis.
Mitotic activity, and cells positive for Ki-67 were identified as important factors in the diagnosis of ovarian fibrosarcoma. Furthermore, FIGO stage and treatment modalities have the potential to be prognostic factors of survival, with BAO followed by adjuvant chemotherapy associated with an improved treatment outcome.
BMC Cancer 10/2010; 10:585. · 3.01 Impact Factor
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ABSTRACT: In an attempt to understand the molecular characterization for the early adenocarcinoma of the uterine cervix, an analysis of gene expression profiles obtained from early adenocarcinoma of the uterine cervix was performed to find those genes most aberrantly expressed.
Total RNA was prepared from 32 samples of early adenocarcinoma of the uterine cervix and 32 paired normal cervix tissues, and hybridized to cancer-associated oligonucleotide microarrays with probe sets complementary to about 1,426 transcripts.
Supervised analysis of gene expression data identified 13 genes that exhibited >2-fold upregulation and 27 genes >2-fold downregulation, respectively, in early adenocarcinoma of the uterine cervix compared to normal cervix. Unsupervised hierarchical clustering of the expression data readily distinguished early adenocarcinoma of the uterine cervix from normal cervix. Two genes (karyopherin alpha 2 and proliferating cell nuclear antigen) were selected randomly for real-time reverse transcription polymerase chain reaction analysis. Both genes were expressed significantly higher in early adenocarcinoma of the uterine cervix than in normal cervix, with p = 0.0003 and <0.0001, respectively. These results were compatible with the microarray data.
This study has revealed several genes that may be highly attractive candidate molecular markers/targets for early adenocarcinoma of the uterine cervix.
Archives of Gynecology 05/2010; 283(4):861-9. · 0.91 Impact Factor
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Guo-Liang Huang,
Bin-Kui Li,
Mei-Yin Zhang,
Hui-Zhong Zhang,
Rong-Rong Wei,
Yun-Fei Yuan,
Ming Shi,
Xiao-Qian Chen, Long Huang,
An-Hua Li,
Bi-Jun Huang,
Hong-Hua Li,
Hui-Yun Wang
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ABSTRACT: To investigate genes around the locus D4S2964 affected by loss of heterozygosity (LOH) and their clinical implications.
Four hundred and forty single nucleotide polymorphisms (SNPs) located at 49 genes around D4S2964 were selected from the National Center for Biotechnology Information website for the SNPs microarray fabrication. LOH of SNPs markers in 112 cases of hepatocellular carcinoma (HCC) tissues and paired adjacent liver tissues were investigated by the SNPs microarray. The correlation between allelic losses with clinicopathological features and overall survival was analyzed.
A fine map of LOH of SNPs in genes around D4S2964 was plotted. The average frequency of LOH in genes was 0.39. A correlation between cirrhosis and the FAL index (fractional allelic loss) was found (P = 0.0202). Larger tumor size was found to be significantly associated with LOH in genes ADP-ribosyltransferase 3 (ART3), nucleoporin 54 kDa (NUP54), scavenger receptor class B, member 2 (SCARB2) and coiled-coil domain containing 158 (CCDC158) (P = 0.043, P = 0.019, P = 0.001, P = 0.037, respectively). Kaplan-Meier analysis showed that patients with LOH in ARD1 homolog B (ARD1B) and septin 11 (SEPT11) had a significantly lower survival rate than those with retention (P = 0.021 and P = 0.004, respectively). A Cox regression model suggested that LOH in ARD1B and SEPT11, respectively, were predictors of the overall survival in HCC (P = 0.006 and P = 0.026, respectively).
LOH in genes around D4S2964 may play an important role in HCC development and progression. LOH in ARD1B and SEPT11 could serve as novel prognostic predictors in HCC patients.
World Journal of Gastroenterology 04/2010; 16(16):2046-54. · 2.47 Impact Factor
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ABSTRACT: Pelvic lymph node metastasis is an important prognostic factor of cervical cancer. The prognosis of cervical cancer patients with common iliac lymph node metastasis is poor, but few systematic studies have been reported . This study was to investigate the characteristics, risk, treatment and prognosis of stage IB-IIB cervical carcinoma patients with common iliac lymph node metastasis.
A total of 960 patients with cervical cancer receiving radical hysterectomy and bilateral pelvic lymphadenectomy were selected from the hospitalized patients in the Cancer Center of Sun Yat-sen University between January 1995 and December 2005, and analyzed retrospectively.
Of the 960 patients, 288 (30.0%) had pelvic lymph node metastasis, and 45 (4.7%) had positive common iliac lymph node. The 5-year overall survival rate (OS) of patients with common iliac lymph node metastasis was 46.1%, and 67.5% in patients with other pelvic lymph node metastasis (P < 0.05). Univariate analysis showed that clinical stage, serum level of squamous cell carcinoma antigen (SCC-Ag) > 4 microg/L before treatment, depth of cervical invasion > or =2/3 and positive parametrial margin were associated with common iliac lymph node metastasis (P < 0.05). Patients with > or =3 pelvic lymph node metastasis (excluding common iliac lymph node) or recurrence had poor prognosis (P < 0.05). Factors predictive of common iliac lymph node metastasis on Logistic forward regression were SCC-Ag > 4 microg/L (P = 0.026, OR = 2.303) before treatment and positive parametrial margin (P = 0.045, OR = 2.634).
Cervical cancer patients with common iliac lymph node metastasis had poorer prognosis compared with patients with other pelvic lymph node metastasis. SCC-Ag >4 microg/L before treatment and positive parametrial margin were the independent predictive factors for common iliac lymph node metastasis of cervical carcinoma. Pelvic lymph node metastasis (excluding common iliac lymph node) > or = 3 or recurrence was prognostic factors for patients with common iliac lymph node metastasis.
Chinese journal of cancer 04/2010; 29(4):431-5.
