Deoxyribonucleic acid ploidy in endometrial carcinoma: a reproducible and valid prognostic marker in a routine diagnostic setting.

Institute of Clinical Medicine, University of Bergen, and Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
American journal of obstetrics and gynecology (Impact Factor: 3.28). 10/2009; 201(6):603.e1-7. DOI: 10.1016/j.ajog.2009.07.029
Source: PubMed

ABSTRACT The objective of the study was to investigate the prognostic impact of deoxyribonucleic acid (DNA) ploidy in endometrial carcinoma in a routine diagnostic series as compared with a research series.
We studied a population-based series of 363 endometrial carcinomas prospectively collected, with long and complete follow-up. The prognostic value of DNA ploidy was investigated in a routine diagnostic series (n=262) and compared with the results from a previous research series (n=101).
The proportion of DNA aneuploid tumors was 21% in the research series and 25% in the routine diagnostic series (P=NS). In both series, DNA aneuploidy was significantly correlated to higher age at diagnosis, nonendometrioid subtype, and high histologic grade. Patients with DNA aneuploid tumors had significantly poorer survival, adjusted for established clinicopathologic prognostic factors.
DNA ploidy estimation in endometrial carcinoma adds independent prognostic information in a routine diagnostic setting.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Microsatellite instability (MSI) and aneuploidy are inversely related phenomena. We tested whether ploidy status influences the clinical impact of MSI in endometrioid endometrial cancer (EEC). We analyzed 167 EECs for MSI and ploidy. Tumors were classified in three categories according to MSI and ploidy status. Associations with clinicopathological and molecular variables, survival, and treatment response were assessed. All MSI tumors (23%) were scored as diploid, and 14% of microsatellite stable (MSS) tumors presented aneuploidy. MSI tumors associated with older age at diagnosis, non-obesity, high histological grade, and advanced surgical stage. MSS-aneuploid tumors also associated with higher grade and advanced stage. In multivariate survival analysis MSI did not influence disease-free survival (DFS) or cancer-specific survival (CSS). However, when just diploid tumors were considered for the analysis, MSI significantly contributed to worse DFS and CSS, and the same was observed for aneuploidy when MSS tumors were analyzed alone. In diploid tumors, a differential response to postoperative radiotherapy (RT) was observed according to MSI, since it predicted poor DFS and CSS in the multivariate analysis. We conclude that ploidy status influences the clinical impact of MSI in EEC. Among diploid tumors those with MSI have poor clinical outcome and respond worse to RT.
    Oncotarget 07/2014; · 6.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective. This study assesses the role of preoperative serum CA125 levels in the planning treatment options for women diagnosed with uterine cancer. Material and Method. Ninety five consecutive patients diagnosed with uterine cancer during a four-year period were identified. Age ranged from 35 to 89 years with a mean age of 69 years. The preoperative CA125 levels were dichotomised at 28 U/mL (using ROC analysis to identify the best discriminating threshold for 5-year survival). This level was then correlated with preoperative prognostic indicators: patient age, tumour grade, and histopathological tumour cell type. Survival data was plotted using Kaplan-Meier curves and analysed using the log-rank test. Univariate and multivariate analysis were performed to identify the predictors of overall survival. Results. The mean age of patients was 69 years (range: 35-89). On univariate analysis, the use of preoperative CA125 levels of greater or less than 28 U/mL correlated significantly with age (P = 0.01), the grade of disease (P = 0.02) and unfavourable tissue type (P = 0.03). This threshold CA125 level had a sensitivity of 75%, specificity of 76%, positive predictive value of 35% and negative predicative value of 96.25%, and a likelihood ratio of 3.12 for predicting nodal disease. Using a threshold of preoperative CA125 level of 28 U/mL (area under curve: 0.60) was also a significant predictor of 5-year survival (log-rank test, P = 0.01). Using Cox multivariate survival analysis to identify predictive preoperative factors overall, unfavourable cell type was the strongest predictor of survival (Chi square = 36.5, df = 4, and P = 0.001), followed by preoperative CA125 level (CA125 > 28 U/mL, P = 0.011) and unfavourable preoperative grade (P = 0.017). Amongst patients with a favourable histological tissue type (endometrioid), preoperative CA125 levels predicted overall survival (Chi square = 6.039, df = 2, P = 0.02); however unfavourable preoperative grade did not (P = 0.5). Overall, at five-year follow-up, while there were no deaths among the women with preoperative serum CA125 less than 12 U/mL, eleven of the twenty-three deaths (47.82%) in the study occurred in women with a preoperative CA125 more than 28 U/mL. Conclusions. A preoperative CA125 assay for women with uterine cancer is a relatively inexpensive, reproducible, and objective test which provides valuable information regarding the risk of metastatic disease and overall likelihood of long term survival. Patients with a low likelihood of metastatic/nodal disease (favourable tissue type and CA125 level < 28 U/mL) and significant comorbidities may benefit from avoiding an extended complete staging procedure. Alternatively, a high level of CA125 may prompt further imaging and multidisciplinary discussions to plan for individualised management and consideration for recruitment to clinical trials.
    Surgery research and practice. 01/2014; 2014:497478.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.
    PLoS Medicine 11/2013; 10(11):e1001551. · 15.25 Impact Factor