Biomarkers in endometrial cancer: Possible clinical applications (Review)

Abstract

Abstract. The number of cases of endometrial cancer has shown a tendency to increase in recent years. Endometrial cancer originates from the endometrium and is classified, based on the development mechanism, into types 1 and 2, which are responsive and non-responsive to estrogen, respectively, and have significantly different gene expression profiles. Studies of genes with abnormal expression in endometrial cancer have identified multiple oncogenes, tumor suppressors, mismatch repair genes, apoptosis-associated genes, levels of hormone receptors and DNA ploidy and aneuploidy as biomarkers of endometrial cancer. The use of these molecules and genes may facilitate accurate diagnosis and prognostic prediction and contribute to individualized treatment. Trials of drugs which target these biomarkers and searches for new biomarkers using cDNA microarrays and RT-qPCR are ongoing and it is likely that these findings can be translated to clinical use. Contents1. Introduction 2. Differences in biomarkers in subtypes of endometrial cancer 3. Oncogenes 4. Tumor suppressors 5. Mismatch repair genes and microsatellite instability 6. Other biomarkers 7. Biomarkers for prognosis and treatment 8. Conclusion IntroductionEndometrial cancer is the seventh most common cancer worldwide in women (1). The incidence differs depending on the region: in developed countries, 10-20 in 100,000 women have endometrial cancer, whereas the incidence is approximately one-tenth this level in developing countries. The number of cases is rapidly increasing in Japan. Obesity, nulliparity and the administration of tamoxifen have been identified as risk factors for endometrial cancer (2).In the last 10 years, numerous studies have aimed to identify tumor biomarkers. The US National Cancer Institute (NCI) defines a biomarker as ʻa biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or diseaseʼ. According to this definition, a biomarker includes not only the proteins normally used as tumor markers, such as CA-125, but also genes and chromosomes. Biomarkers of endometrial cancer that have been identified include the K-ras, HER2/neu, epithelial growth factor receptor (EGFR), phosphatidylinositol 3-kinase catalytic subunit (PI3KCA) and fibroblast growth factor receptor 2 (FGFR2) oncogenes; the phosphatase and tensin homolog (PTEN), p53, p21 and cyclin-dependent kinase inhibitor 2A (CDKN2A) cancer suppressor genes; the hMLH1, hMSH2, hMSH6, PMS1 and PMS2 mismatch repair genes; Ki-67, an index of cell proliferation; BCL2-associated X protein (Bax), an apoptosis promotor gene; Bcl-2, an apoptosis suppressor; expression levels of estrogen and progesterone receptors; microvascular density (MVD); and vascular endothelial growth factor A (VEGF-A), which are all indices of angiogenesis; expression changes in E/P-cadherin and β-catenin, which are associated with infiltration and metastatic capacity; and ploidy and aneuploidy of DNA. The characteristics and functions of each of these bioma...

The role of HE4 and CA125 in differentiation between malignant and non-malignant endometrial pathologies

“…In 2012, a total of 320 000 new cases were diagnosed in the world [1]. The incidence rate is higher in the developed countries [1,2]. The majority of EC cases are diagnosed in the early stages due to early symptommaticity.…”

Biological markers with potential clinical value in endometrial cancer — review of the literature

“…A wide variety of proposed biomarkers have been examined for EC of the respective subtype. Defects in DNA mismatch repair genes, microsatellite instability, and mutations in the PTEN and K-ras and/or B-catenin genes are mutated in high rates for type I, whereas alteration in the p53 suppressor gene with mutation of Her-2/neu are commonly observed in type II [2,3]. Based on the significantly different gene expression profile, one can suspect that the two types may have distinct underlying etiologies, which in turn is responsible for the pathogenesis and progression [3].…”

“…Defects in DNA mismatch repair genes, microsatellite instability, and mutations in the PTEN and K-ras and/or B-catenin genes are mutated in high rates for type I, whereas alteration in the p53 suppressor gene with mutation of Her-2/neu are commonly observed in type II [2,3]. Based on the significantly different gene expression profile, one can suspect that the two types may have distinct underlying etiologies, which in turn is responsible for the pathogenesis and progression [3]. For that reason, these biomarkers are currently used as diagnostic clues representing the most common basis for prognostic estimation of this gynaecological malignancy [2].…”

“…By contrast, type II (non-endometrioid cancer) follows the estrogen-unrelated pathway, which seems to arise from a background of atrophic endometrium. Type II tumors are commonly diagnosed in older postmenopausal women, and are generally less differentiated accounting for a poor prognostic outcome [2,3]. A wide variety of proposed biomarkers have been examined for EC of the respective subtype.…”

“…However, women encountering more advanced or recurrent disease will have an extremely poor clinical outcome. Thus, renewed research focus on better understanding the molecular changes associated with EC, which is mainly promoted by the dramatic increase in incidence observed in the recent years [3]. In contrast to cervical cancer, there is still insufficient evidence to recommend any cost-effective screening method in women with average to high risk and without symptom presentation [1].…”