Biomarker Commons

Advancements in the use of blood tests for cancer screening in women at high risk for endometrial and breast cancer.

Future Oncol. 2011 Dec;7(12):1399-414

Authors: Ambeba E, Linkov F

Abstract
Several years ago, it was argued that the identification of serum biomarkers is one of the most promising approaches for the detection of early-stage malignant or even premalignant lesions. In this review, the need to establish better monitoring protocols is described for obese women who are at higher risk for the development of malignancies commonly associated with excess weight; specifically endometrial and postmenopausal breast cancer. These cancers have been chosen for this review article as our aim was to focus on female cancers that have been linked with obesity. Cancer screening is essential in detecting disease in its earliest stage in order to reduce morbidity and mortality; however, effective screening is not available for many cancer types. Even for cancers that have effective screening protocols available, there are barriers to screening in obese individuals, such as reduced mobility and embarrassment. These barriers often delay screening in these vulnerable population groups, leading to detection of the disease at a more advanced stage and ultimately leading to a poorer prognosis. As of today, biomarkers do not replace but augment imaging and other existing screening approaches. Future development of blood- or urine-based biomarkers as a way to screen individuals at high risk for certain cancers may prove to be an excellent method for overcoming the barriers that individuals at high risk are facing today. The overall purpose of this manuscript is to provide an overview of screening techniques and to identified barriers and alternate biomarker-based approaches for improvement of endometrial and breast cancer screening in obese women.

PMID: 22112316 [PubMed - indexed for MEDLINE]

Avian SERPINB11 gene: a marker for ovarian endometrioid cancer in chickens.

Exp Biol Med (Maywood). 2012 Feb 1;237(2):150-9

Authors: Lim W, Kim JH, Ahn SE, Jeong W, Kim J, Bazer FW, Han JY, Song G

Abstract
As serine and cysteine proteinase inhibitors, serpins, such as SERPINB5, cause ovarian, colorectal and pancreatic adenocarcinomas. We identified SERPINB11 as a novel estrogen-induced gene in chickens during oviduct development. The chicken is a unique animal model for research on human ovarian cancer, because it spontaneously develops epithelial cell-derived ovarian cancer as in women. Therefore, this study investigated the expression pattern, CpG methylation status, and miRNA regulation of the SERPINB11 gene in normal and cancerous ovaries from chickens. Our results indicate that SERPINB11 is most abundant in the glandular epithelium of endometrioid adenocarcinoma of cancerous, but not normal, ovaries of hens. In addition, bisulfite sequencing revealed that about 30% of -110 CpG sites are methylated in ovarian cancer cells, whereas -110 CpG sites are demethylated in normal ovarian cells. Next, we determined whether miR-1582 influences SERPINB11 expression via its 3'UTR and found that it does not directly target the 3'UTR of SERPINB11 mRNA. Therefore, it is unlikely that post-transcriptional regulation influences SERPINB11 expression in the chicken ovary. On the other hand, in human ovarian cancer cells such as OVCAR-3, SKOV-3 and PA-1 cells, immunoreactive SERPINB11 protein was predominant in the cytoplasm and had a similar expression pattern to that in chicken ovarian cancer cells. Collectively, these results suggest that SERPINB11 is a biomarker for chicken ovarian endometrioid carcinoma that could be used for diagnosis and monitoring effects of therapies for the disease in women.

PMID: 22289513 [PubMed - indexed for MEDLINE]

[Clinical characteristics of borderline ovarian tumors and stage I epithelial ovarian cancer: an analysis of 143 cases].

Beijing Da Xue Xue Bao. 2011 Feb 18;43(1):123-8

Authors: Zhao Y, Wang Y, Shen Dh, Song Rn, Xu Q, Li Y, Cui H, Tang J, Wei Lh

Abstract
OBJECTIVE: To study the clinical pathological characteristics and high risk factors for borderline ovarian tumor (BOT) and stage I epithelial ovarian cancer (EOC).
METHODS: A total of 91 patients with BOT and 52 patients with stage IEOC who were diagnosed and treated in the Department of Gynecology, Peking University People's Hospital from November 2002 to May 2010 were recruited in this study. The patients' clinical characteristics were reviewed respectively and compared between the two groups.
RESULTS: The women in BOT group were significantly younger than those in EOC group (41.16 ± 14.95 vs. 50.90 ± 14.37,P<0.01). Compared with women with BOT, women with EOC were more likely to be post-menopausal(42.3% vs. 23.1%,P=0.016) and more with family history of malignant tumors (26.9% vs. 13.2%,P=0.04).There were no significant differences in the size of tumors and the serum level of tumor markers. But the size of solid portion of the tumor of EOC was significantly larger than that of BOT(P<0.01). The extent of the increase of CP2 among the patients with EOC was higher than that among the patients with BOT(256.99 vs. 116.59, P=0.028). There was a statistically significant difference between the two groups in tumors' histopathological type(P<0.01). The serous and mucous tumors were more common in EOC group (90.1%, 82/91). In contrary, endometrioid, clear cells and mixed epithelial cancers were more common in EOC group than serous and mucous cancers (44.2%, 23/52).
CONCLUSION: Although the clinical presentation of patients with stage I EOC was similar to that of those with BOT, there were significant differences in the patients' age, post-menopausal or not, family history of malignant tumors, size of solid portion of tumors, extent of the increase of the tumor biomarker, especially of CP2 and tumors histopathological type. These clinicopathological characteristics might be helpful for us to make different diagnosis.

PMID: 21321635 [PubMed - indexed for MEDLINE]

Status and significance of CpG island methylator phenotype in endometrial cancer.

Gynecol Obstet Invest. 2011;72(3):183-91

Authors: Zhang QY, Yi DQ, Zhou L, Zhang DH, Zhou TM

Abstract
BACKGROUND: Endometrial cancer is a common gynecologic malignant disease, but patients with advanced disease have a poor prognosis. The CpG island methylator phenotype (CIMP) involves hypermethylation targeted toward the promoters of multiple genes.
OBJECTIVE: To investigate the role of epigenetic aberration of tumor-related genes in endometrial cancer.
METHODS: The promoter methylation status of 5 genes was examined in 35 endometrial cancer tissues, 15 matched adjacent normal endometrial tissues (NET) from the same cancer patients, and 22 benign endometria from unaffected patients by methylation-specific PCR. CIMP positivity (CIMP+) was defined as concordant methylation of ≥3 genes.
RESULTS: The methylation frequency of promoters for the 5 genes in the cancer tissues ranged from 37% for P16 to 57% for P14. Cancer and benign endometria, but not cancer and adjacent NET, significantly differed in methylation of P14, P16, ER, COX-2 and RASSF1A (p < 0.05). CIMP+ was frequent in cancer and adjacent NET (46 and 47%, respectively; p > 0.05), but absent in benign endometria. Moreover, CIMP+ was significantly correlated with methylation of P16 and COX-2 (r = 0.673 and 0.662, respectively; p < 0.001).
CONCLUSION: CIMP+ is an important and frequent epigenetic event in endometrial cancer or adjacent NET, and may be a biomarker for predicting early carcinogenesis. COX-2 is a good representative gene of CIMP+ in this cancer.

PMID: 21968189 [PubMed - indexed for MEDLINE]

Prognostic impact of prechemotherapy serum levels of HER2, CA125, and HE4 in ovarian cancer patients.

Int J Gynecol Cancer. 2011 Aug;21(6):1040-7

Authors: Steffensen KD, Waldstrøm M, Brandslund I, Jakobsen A

Abstract
OBJECTIVE: Human epididymis protein 4 (HE4) has attracted a lot of interest as a relatively novel biomarker for ovarian carcinoma. Research focus has been directed at HE4 as a diagnostic tool with potential for better triage of women with adnexal masses but the prognostic aspect of HE4 in ovarian cancer patients remains to be elucidated. The aim of the present study was to investigate the prognostic value of prechemotherapy serum HER2, cancer antigen 125 (CA125), and HE4 levels in ovarian cancer patients receiving standard combination chemotherapy.
METHODS: Serum from 139 patients with newly diagnosed ovarian cancer was analyzed for HER2, CA125, and HE4 using enzyme-linked immunosorbent assay assays. Samples were collected just before first-line chemotherapy, and all patients were treated with carboplatin-paclitaxel combination chemotherapy.
RESULTS: Increasing levels of serum HE4 (grouped into quartiles) was significantly associated with worse progression-free survival (PFS) (P < 10) and overall survival (P < 10). After adjustment in the Cox model, HE4 serum levels remained an independent prognostic parameter for PFS, with a hazard ratio of 1.77 (95% confidence interval, 1.03-3.04; P = 0.040) for patients with HE4 levels above the median compared with patients with HE4 levels below the median. The shorter PFS for patients with high levels of HE4 also translated into an independent significant difference in overall survival (hazard ratio, 3.17 [95% confidence interval, 1.41-7.10]; P = 0.005).Serum HER2 and CA125 levels did not demonstrate an independent prognostic value.
CONCLUSIONS: High levels of serum HE4 is a strong and independent indicator of worse prognosis in epithelial ovarian cancer patients.

PMID: 21738039 [PubMed - indexed for MEDLINE]

Determination of CA-125 levels in the serum, cervical and vaginal secretions, and endometrium in Chinese women with precancerous disease or endometrial cancer.

Med Sci Monit. 2011 Nov;17(11):CR618-625

Authors: He SM, Xing F, Sui H, Wu Y, Wang Y, Wang D, Chen G, Kong Z, Zhou SF

Abstract
BACKGROUND: Serum CA-125 has been used as a biomarker of gynecological tumors. In this study, we investigated the CA-125 levels in cervical and vaginal secretions from Chinese patients with endometrial polyps, hyperplasia and carcinoma in comparison with those in endometrium and serum.
MATERIAL/METHODS: An electro-chemiluminescent immunoassay was utilized to determine the levels of CA-125 in 51 healthy Chinese women and 97 patients with polyps, hyperplasia or endometrial cancer. An immunohistochemistry method was used to detect endometrial CA-125 expression in 242 subjects.
RESULTS: Our study demonstrated that serum CA-125 levels were much lower than those in cervical and vaginal secretions in healthy and diseased women. The levels of CA-125 in serum, and cervical and vaginal secretions were significantly increased in complex hyperplasia and endometrial cancer. The increase of CA-125 content in serum, cervical and vaginal secretions was lesser significant in grade 3 cancer than that in grade 1 and 2 cancer. Generally, serum CA-125 levels correlated with those in cervical and vaginal secretions and CA-125 content in cervical secretion correlated with that in vaginal secretion. There was only a weak CA-125 expression in normal endometrium and simple endometrial hyperplasia. There was a significant difference in CA-125 expression among patients with pathological grade 1, 2 and 3 of endometrial carcinoma.
CONCLUSIONS: Endo.metrial CA-125 expression together with its levels in the serum and cervical and vaginal secretions can be used as a potential biomarker in the diagnosis of precancerous diseases and endometrial carcinoma.

PMID: 22037740 [PubMed - indexed for MEDLINE]

Dysregulation of microRNA-204 mediates migration and invasion of endometrial cancer by regulating FOXC1.

Int J Cancer. 2012 Mar 1;130(5):1036-45

Authors: Chung TK, Lau TS, Cheung TH, Yim SF, Lo KW, Siu NS, Chan LK, Yu MY, Kwong J, Doran G, Barroilhet LM, Ng AS, Wong RR, Wang VW, Mok SC, Smith DI, Berkowitz RS, Wong YF

Abstract
MicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3'-untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression- and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.

PMID: 21400511 [PubMed - indexed for MEDLINE]

Synuclein-γ (SNCG) protein expression is associated with poor outcome in endometrial adenocarcinoma.

Gynecol Oncol. 2012 Jan;124(1):148-52

Authors: Mhawech-Fauceglia P, Wang D, Syriac S, Godoy H, Dupont N, Liu S, Odunsi K

Abstract
OBJECTIVE: Synuclein-γ (SNCG) is a marker for adverse and aggressive disease in breast cancer. In previous study, we found SNCG mRNA to be overexpressed in uterine serous carcinoma compared to uterine endometrioid adenocarcinoma. The aim of this study is to explore the prognostic value of SNCG in patients with endometrial cancer.
METHODS: 279 endometrial cancer patients were retrieved from the archives. The tissue paraffin blocks were stained for SNCG antibody and its expression was correlated with clinicopathological prognostic factors.
RESULTS: There was a positive association between SNCG(+) immunoexpression and tumor grade, tumor stage, type II carcinomas, deep myometrial invasion and lymphovascular invasion. A correlation between SNCG(+) and adverse outcomes, such as shorter overall survival (OS) and disease free survival (DFS), was also detected. Following adjuvant therapy (radiation and chemotherapy or chemotherapy alone), we observed a difference in 5years DFS rate between SNCG(+) (41.6%) and SNCG(-) patients (59.5%).
CONCLUSION: Overexpression of SNCG seemed to be a predictor biomarker for aggressive tumor behavior and adverse outcome in patients with endometrial cancer. Future exploration of SNCG as a potential therapeutic target for selected patients could be of interest.

PMID: 22015044 [PubMed - indexed for MEDLINE]

Utility of tumor marker HE4 to predict depth of myometrial invasion in endometrioid adenocarcinoma of the uterus.

Int J Gynecol Cancer. 2011 Oct;21(7):1185-90

Authors: Moore RG, Miller CM, Brown AK, Robison K, Steinhoff M, Lambert-Messerlian G

Abstract
OBJECTIVE: The purpose of this pilot study was to determine whether the biomarker human epididymis protein 4 (HE4) correlates with depth of myometrial invasion, histologic grade, lymph vascular space invasion, positive cytologic washings, and nodal metastases in patients with endometrioid adenocarcinoma of the uterus.
METHODS: This was a prospective, observational study in women with biopsy-proven endometrioid adenocarcinoma. Concentrations of HE4 were assessed before surgery, and all surgical specimens were reviewed by dedicated gynecologic pathologists.
RESULTS: Included were a total of 96 women with endometrioid adenocarcinomas of the uterus, most (77%) with stage I disease. Levels of serum HE4 greater than 70 pM displayed a sensitivity of 94% and a negative predictive value of 97% in identifying stage IA (<50% myometrial invasion) versus stage IB (≥ 50% myometrial invasion) tumors and a sensitivity of 82% and negative predictive value of 82% versus all more advanced tumors.
CONCLUSIONS: Human epididymis protein 4 may be a useful marker preoperatively in the clinical decision process for determining the need for lymph node dissection in women with endometrioid endometrial cancer.

PMID: 21720250 [PubMed - indexed for MEDLINE]