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Int. J. Mol. Sci. 2013, 14, 12123-12137; doi:10.3390/ijms140612123 International Journal of Molecular Sciences ISSN 1422-0067 Review Candidate Biomarkers for Genetic and Clinicopathological Diagnosis of Endometrial Cancer Kouji Banno *, Yuya Nogami, Iori Kisu, Megumi Yanokura, Kiyoko Umene, Kenta Masuda, Yusuke Kobayashi, Wataru Yamagami, Nobuyuki Susumu and Daisuke Aoki Department of Obstetrics and Gynecology, School of Medicine, Keio University, Shinan
   Int. J. Mol. Sci.   2013 , 14 , 12123-12137; doi:10.3390/ijms140612123 International Journal of Molecular Sciences ISSN 1422-0067  Review Candidate Biomarkers for Genetic and Clinicopathological Diagnosis of Endometrial Cancer Kouji Banno *, Yuya Nogami, Iori Kisu, Megumi Yanokura, Kiyoko Umene, Kenta Masuda, Yusuke Kobayashi, Wataru Yamagami, Nobuyuki Susumu and Daisuke Aoki Department of Obstetrics and Gynecology, School of Medicine, Keio University, Shinanomachi 35 Shinjuku-ku, Tokyo 160-8582, Japan; E-Mails: (Y.N.); (I.K.); (M.Y.); (K.U.); (K.M.); (Y.K.); (W.Y.); (N.S.); (D.A.) * Author to whom correspondence should be addressed; E-Mail:; Tel.: +81-3-3353-1211; Fax: +81-3-3226-1667.  Received: 27 February 2013; in revised form: 15 May 2013 / Accepted: 20 May 2013 /  Published: 6 June 2013 Abstract:  The recent increase in the frequency of endometrial cancer has emphasized the need for accurate diagnosis and improved treatment. The current diagnosis is still based on conventional pathological indicators, such as clinical stage, tumor differentiation, invasion depth and vascular invasion. However, the genetic mechanisms underlying endometrial cancer have gradually been determined, due to developments in molecular biology, leading to the possibility of new methods of diagnosis and treatment planning. New candidate  biomarkers for endometrial cancer include those for molecular epigenetic mutations, such as microRNAs. These biomarkers may permit earlier detection of endometrial cancer and  prediction of outcomes and are likely to contribute to future personalized therapy for endometrial cancer. Keywords:  endometrial cancer; microsatellite instability; MSH6; DNA hypermethylation; CHFR; microRNA; Lynch syndrome; PTEN; K-ras; CA125 OPEN ACCESS   Int. J. Mol. Sci.   2013 , 14  12124 1. Introduction Endometrial cancer accounts for 70% to 80% of cases of primary malignant disease in the uterus in the United States [1]. In contrast, cervical cancer accounts for most malignant uterine disease in Asia,  but cases of endometrial cancer have increased, due to improved screening and Westernized dietary habits. Thus, the Japan Society of Obstetrics and Gynecology (JSOG) reported that endometrial cancer had increased from 976 patients in 1983 to 4267 in 2005 and 6113 in 2009. This most recent number accounts for about half of all cases of malignant uterine disease [2,3] and emphasizes the need to improve diagnosis and treatment of endometrial cancer. Recent advances in molecular biology have made major contributions to the understanding of malignant diseases and development of diagnostic technology. Mutation of the epidermal growth factor receptor (  EGFR ) gene is an important biomarker for prediction of the effect of gefitinib, a molecular-targeted drug. Personalized medicine based on individual differences among patients is attainable using a treatment strategy with anticancer drugs chosen based on prediction of effects and adverse reactions using these biomarkers. Genetic studies of endometrial cancer have established relationships between carcinogenesis and gene mutations. Thus, mutation of  phosphatase and tensin homolog deleted from chromosome10 (  PTEN  ), a tumor suppressor gene, is frequently detected in endometrioid adenocarcinoma and that of  p53 is often detected in cancer in other tissue types. Abnormalities that cannot be explained by gene mutation are also frequently found in malignant diseases, including endometrial cancer. These include epigenetic mutations, which produce abnormal gene expression without changes in the base sequence of genomic DNA. microRNAs (miRNAs), which are associated with regulation of gene expression, are also of interest, due to their involvement in mechanisms associated with onset of malignant disease. Familial aggregation of endometrial cancer is also a focus, and patients with Lynch syndrome (hereditary non-polyposis colorectal cancer: HNPCC) are often complicated with both colorectal and hereditary endometrial cancer. Lynch syndrome is caused  by germ cell mutation of mismatch repair (MMR) genes that are strongly related to endometrial cancer. These findings are likely to promote development of new treatment for endometrial cancer. 2. Genetic Abnormalities in Endometrial Cancer Endometrial cancer is divided into two types [4–6]. The type 1 form occurs in patients with typical risk factors, including endocrine disorders, such as obesity and excessive estrogen, and accounts for about 80% of cases of endometrial cancer. The type 1 cancer is well-differentiated endometrioid adenocarcinoma with relatively good outcomes and frequently occurs in perimenopausal women. The type 2 form occurs in patients without the above risk factors and includes poorly differentiated endometrioid adenocarcinoma, serous adenocarcinoma, mucinous adenocarcinoma and clear cell adenocarcinoma. This form has poor outcomes and tends to develop in elderly women. Type 1 endometrial cancer is most commonly characterized by mutation of  PTEN  , a tumor suppressor; and also by mutations in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog   (  K-ras ),  β  -catenin ,  phosphatidylinositol-4 , 5-bisphosphate 3-kinase ,  catalytic subunit alpha  (  PIK3CA )   and  phosphatidylinositol 3-kinase (  PIK3 ) .  Some cases also have inactivation of mutS homolog 6   (  MSH6  ), which is associated with microsatellite instability (MSI) [7,8]. Inherited or somatically acquired   Int. J. Mol. Sci.   2013 , 14  12125 mutations of MSH6, although relatively uncommon in endometrial cancers in general, are often seen in MSI endometrial cancer. Type 2 endometrial cancer shows mutations of  p53  and  p16  , reduced expression of  E-cadherin  and overexpression of human epidermal growth factor receptor 2 (  Her-2/neu ) (Table 1 and Figure 1) [7,9].   Table 1.  Genetic mutations in Type 1 and 2 endometrial cancer. Genetic alteration Type 1 (%) Type 2 (%)  PTEN   inactivation 50–80 10  K-ras  mutation 15–30 0–5    -catenin  mutation 20–40 0–3 Microsatellite instability 20–40 0–5  p53  mutation 10–20 80–90  HER-2/neu  10–30 40–80  p16   inactivation 10 40  E-cadherin 10–20 60–90 Figure 1.  Genetic mutations in endometrial cancer. 3. Epigenetic Aberrant Methylation in Endometrial Cancer Epigenetic mutations cause abnormal gene expression without changes in the DNA base sequence. Epigenetic mechanisms regulate downstream gene expression through aberrant hypermethylation of CpG islands in promoter regions, hypomethylation of entire genomes and histone acetylation [10].   Aberrant hypermethylation of gene promoters causes transcriptional silencing of oncogenes, resulting in abnormal proliferation of cells and carcinogenesis (Figure 2). The nucleosome, a unit of chromatin, consists of a core tetramer of histone pairs of H3-H4 dimers that form an octamer with 2 histone H2A-H2B dimers, with approximately 147 bp of DNA wrapping around the octamer about 1.75-times. Structural analysis of the nucleosome shows that the  N  -termini of histones  protrude to sites outside the DNA. The  N   (and C  )-terminal domains of the histone core proteins (histone tails) undergo various posttranslational modifications, including acetylation, methylation, ubiquitination and phosphorylation. Combinations of histone modifications define the status of the activation of the chromosome and positional information, and therefore, this is considered to be a kind of genetic code. Histone acetylation removes positive charges of lysine residues and decreases electrostatic interactions   Int. J. Mol. Sci.   2013 , 14  12126 with the negatively charged DNA. This reduces the affinity of the histone for the DNA and leads to conversion of heterochromatin to euchromatin, allowing cofactors to interact with DNA and increase transcriptional activity. Figure 2.  Mechanism of gene inactivation by aberrant methylation. Histone acetylation and deacetylation are catalyzed by histone acetyl transferase (HAT) and histone deacetylase (HDAC) enzymes, respectively. Histone acetylation activates binding of transcription factors and enhances transcriptional activation, while deacetylation inhibits transcription. The 18 known HDACs are classified into Classes I to IV based on amino acid sequence homology at sites of enzyme activity [11]. Class I enzymes (HDAC 1, 2, 3 and 8) are homologs of yeast Rpd3 that are present mainly in nuclei and are constitutively expressed in many cells and tissues. Class II enzymes (HDAC 4, 5, 6, 7, 9 and 10) are homologs of yeast Hda1 and are mainly present in the brain, myocardium and skeletal muscles. Class II is further classified into Classes IIa (HDAC 4, 5, 7 and 9) and IIb (HDAC 6 and 10). Class III enzymes are Sir2 homologs and include SIRT 1, 2, 3, 4, 5, 6 and 7. Class IV currently includes HDAC11 alone. The relationship between HDAC expression and endometrial malignant transformation remains unclear. Class I HDAC expression in the endometrium and in endometrial cancer has recently  been shown for the first time [12,13]. HDAC expression occurs throughout the menstrual cycle, but HDAC3 expression decreases from menstrual days six to 10, suggesting that HDAC expression is involved in endometrial differentiation [12]. Endometrial cancer with strong Class I HDAC expression may have a poor prognosis [13], and it is of note that many studies have shown antitumor effects of HDAC inhibitors, including in endometrial cancer. MSI is a phenomenon in which microsatellite repeat sequences in tumor tissues differ from those in non-tumor tissues, due to dysfunction of the repair of base sequence errors in DNA replication. MSI occurs in Lynch syndrome, is commonly used in screening and has been detected in 20% of patients with sporadic endometrial cancer [14,15]. Inactivation of   MLH1 , a DNA MMR gene, is common in endometrial cancer, due to hypermethylation in CpG islands of gene promoters, and is a major cause of MSI. In a study of 93 patients who underwent radiotherapy after total extrafascial hysterectomy, Bilbao et al  . [16] found 20 MSI-positive cases (22%) and a relationship of MSI with progression (  p  = 0.04) and
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