Epigenetic Modification of HAND2 May Be Associated With the Development of Endometrial Cancer
In a study reported in the journal PLoS One, Allison Jones, MD, of the Elizabeth Garrett Anderson Institute for Women’s Health, University College London, and colleagues analyzed the functional role of epigenetic factors in endometrial cancer development. They found that HAND2 methylation could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response.
Study Details
Dr. Jones and colleagues analyzed DNA methylation in 23 patients with normal endometrial tissue and 64 patients with endometrial cancer. Of all of the factors examined that had an association with endometrial cancer—including p53, PTEN, and PIK3CA mutations—HAND2 methlyation was observed most often, occurring in over 90% of endometrial cancers. The HAND2 gene is often expressed in the endometrial stroma, where it is known to suppress the production of fibroblast growth factors.
Validation of these findings was accomplished via analysis of gene methylation in multiple sets of tissue samples from 272 additional women. Overall, six types of sets were examined. The first set included frozen tissue from 23 patients with normal endometrial tissue and 64 patients with cancerous endometrial tissue. The second set comprised mRNA from 79 women with endometrioid stage I endometrial cancer and 12 postmenopausal women with atrophic endometrium. The third set contained frozen tissue from 118 women with endometrial cancer and 27 without.
The remaining sets incorporated cotton swabs from 48 women with various stages of endometrial cancer; 37 archived paraffin tissue samples comprising four histologic subsets (normal endometrium from women with hysterectomy for benign diseases, unaffected normal endometrium from women with complex atypical hyperplasia, affected complex atypical hyperplasia, and endometrioid endometrial cancer); and biopsied tissue from 42 women who underwent hysteroscopy. A conditional knockout mouse model was utilized to measure the functional relevance of HAND2 suppression.
Suppression of HAND2 mRNA Levels
As previously noted, the investigators initially found that HAND2 methylation has great importance in the development of endometrial cancer. They noted that HAND2 methylation is already increased in premalignant endometrial lesions compared with normal endometrium. Indeed, almost all endometrial cancer samples were strongly methylated, demonstrating suppression of HAND2 mRNA levels (P < .001). Conversely, all of the noncancerous tissue samples had high HAND2 mRNA expression levels.
In addition, the investigators found that HAND2 methylation in noncancerous hyperplastic endometrium was predictive of response to progesterone therapy. This was validated via 42 biopsy samples that were pretreated with progesterone. Moreover, women who did not show a response to progesterone therapy had higher HAND2 methylation levels than women who had a response to progesterone therapy.
In regard to the influence of age in relationship to HAND2 levels in postmenopausal women, the investigators noted that absence of this gene initiated preneoplastic alterations with increasing age in mouse models. A significant increase in the gland/stroma ratio and an irregularity in the shape and size of the glands was also observed with increasing age.
Classic Tumor-Suppressor Gene
From the results of their study, the researchers suggested that analysis of HAND2 levels could be used as a test to detect endometrial cancer and to predict response to preventive treatment.
The authors concluded: “HAND2 exhibits all the features of a classical tumour suppressor gene: [i]t is activated by progesterone…; it suppresses estrogen-mediated signals that stimulate the endometrial epithelium and are known to be involved in endometrial carcinogenesis; it is robustly suppressed in endometrial cancer by [methylation] of DNA; [and] it is the hub of a differential methylation hotspot that ranked top among all hotspots in an integrative epigenome-interactome network analysis.”
Martin Widschwendter, MD, of the Elizabeth Garrett Anderson Institute for Women’s Health, University College London, is the corresponding author for the article in PLoS One.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
