Discovery and validation of methylation markers for endometrial cancer - PubMed (original) (raw)

. 2014 Oct 15;135(8):1860-8.

doi: 10.1002/ijc.28843. Epub 2014 Mar 31.

Jamie N Bakkum-Gamez, J Keith Killian, Joshua Sampson, Richard Guido, Andrew Glass, Lisa Adams, Patricia Luhn, Louise A Brinton, Brenda Rush, Lori d'Ambrosio, Munira Gunja, Hannah P Yang, Montserrat Garcia-Closas, James V Lacey Jr, Jolanta Lissowska, Karl Podratz, Paul Meltzer, Viji Shridhar, Mark E Sherman

Affiliations

Discovery and validation of methylation markers for endometrial cancer

Nicolas Wentzensen et al. Int J Cancer. 2014.

Abstract

The prognosis of endometrial cancer is strongly associated with stage at diagnosis, suggesting that early detection may reduce mortality. Women who are diagnosed with endometrial carcinoma often have a lengthy history of vaginal bleeding, which offers an opportunity for early diagnosis and curative treatment. We performed DNA methylation profiling on population-based endometrial cancers to identify early detection biomarkers and replicated top candidates in two independent studies. We compared DNA methylation values of 1,500 probes representing 807 genes in 148 population-based endometrial carcinoma samples and 23 benign endometrial tissues. Markers were replicated in another set of 69 carcinomas and 40 benign tissues profiled on the same platform. Further replication was conducted in The Cancer Genome Atlas and in prospectively collected endometrial brushings from women with and without endometrial carcinomas. We identified 114 CpG sites showing methylation differences with p values of ≤ 10(-7) between endometrial carcinoma and normal endometrium. Eight genes (ADCYAP1, ASCL2, HS3ST2, HTR1B, MME, NPY and SOX1) were selected for further replication. Age-adjusted odds ratios for endometrial cancer ranged from 3.44 (95%-CI: 1.33-8.91) for ASCL2 to 18.61 (95%-CI: 5.50-62.97) for HTR1B. An area under the curve (AUC) of 0.93 was achieved for discriminating carcinoma from benign endometrium. Replication in The Cancer Genome Atlas and in endometrial brushings from an independent study confirmed the candidate markers. This study demonstrates that methylation markers may be used to evaluate women with abnormal vaginal bleeding to distinguish women with endometrial carcinoma from the majority of women without malignancy.

Keywords: biomarker; early detection; endometrial cancer; methylation; vaginal bleeding.

Published 2014. This article is a US government work and, as such, is in the public domain in the United States of America.

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Conflict of interest statement

The authors have declared no conflicts of interest.

Figures

Figure 1

Figure 1

Unsupervised hierarchical clustering of 148 endometrial carcinomas and 23 benign endometrial tissues Unsupervised hierarchical clustering was based on the 25% most variable probes within the discovery set. Methylation probes are in rows, endometrial cancers (blue) and normal endometrial tissues (yellow) are in columns. The dendrogram shows the Euclidean distance between individual samples.

Figure 2

Figure 2

Receiver Operator Characteristic curve analysis to discriminate endometrial carcinoma from benign endometrial tissue using methylation markers Receiver-operating characteristics (ROC) curves with areas under the curve (AUC) are shown for discrimination between endometrial carcinomas and normal endometrial tissues using methylation markers. (A) Independent replication of all genes (black line) and the top 8 candidate genes (red dashed line) from the discovery effort (including 148 carcinomas from PECS and 25 normal tissues from BRTE) in the replication study (including 69 carcinomas from EH and 40 normal tissue from BRTE). (B) Independent replication of seven candidate genes in prospectively collected endometrial brushings from women with and without endometrial carcinoma. Colored lines show ROC curves for individual genes and solid black line shows the ROC curve for all seven genes combined.

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