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The genomics and genetics of endometrial cancer
O'Hara AJ, Bell DW
Advances in Genomics and Genetics , 2012, DOI: http://dx.doi.org/10.2147/AGG.S28953
Abstract: enomics and genetics of endometrial cancer Review (2452) Total Article Views Authors: O'Hara AJ, Bell DW Published Date March 2012 Volume 2012:2 Pages 33 - 47 DOI: http://dx.doi.org/10.2147/AGG.S28953 Received: 07 December 2011 Accepted: 04 January 2012 Published: 07 March 2012 Andrea J O’Hara, Daphne W Bell National Human Genome Research Institute, Cancer Genetics Branch, National Institutes of Health, Bethesda, MD, USA Abstract: Most sporadic endometrial cancers (ECs) can be histologically classified as endometrioid, serous, or clear cell. Each histotype has a distinct natural history, clinical behavior, and genetic etiology. Endometrioid ECs have an overall favorable prognosis. They are typified by high frequency genomic alterations affecting PIK3CA, PIK3R1, PTEN, KRAS, FGFR2, ARID1A (BAF250a), and CTNNB1 (β-catenin), as well as epigenetic silencing of MLH1 resulting in microsatellite instability. Serous and clear cell ECs are clinically aggressive tumors that are rare at presentation but account for a disproportionate fraction of all endometrial cancer deaths. Serous ECs tend to be aneuploid and are typified by frequent genomic alterations affecting TP53 (p53), PPP2R1A, HER-2/ERBB2, PIK3CA, and PTEN; additionally, they display dysregulation of E-cadherin, p16, cyclin E, and BAF250a. The genetic etiology of clear cell ECs resembles that of serous ECs, but it remains relatively poorly defined. A detailed discussion of the characteristic patterns of genomic alterations that distinguish the three major histotypes of endometrial cancer is reviewed herein.
The genomics and genetics of endometrial cancer  [cached]
O'Hara AJ,Bell DW
Advances in Genomics and Genetics , 2012,
Abstract: Andrea J O’Hara, Daphne W Bell National Human Genome Research Institute, Cancer Genetics Branch, National Institutes of Health, Bethesda, MD, USAAbstract: Most sporadic endometrial cancers (ECs) can be histologically classified as endometrioid, serous, or clear cell. Each histotype has a distinct natural history, clinical behavior, and genetic etiology. Endometrioid ECs have an overall favorable prognosis. They are typified by high frequency genomic alterations affecting PIK3CA, PIK3R1, PTEN, KRAS, FGFR2, ARID1A (BAF250a), and CTNNB1 (β-catenin), as well as epigenetic silencing of MLH1 resulting in microsatellite instability. Serous and clear cell ECs are clinically aggressive tumors that are rare at presentation but account for a disproportionate fraction of all endometrial cancer deaths. Serous ECs tend to be aneuploid and are typified by frequent genomic alterations affecting TP53 (p53), PPP2R1A, HER-2/ERBB2, PIK3CA, and PTEN; additionally, they display dysregulation of E-cadherin, p16, cyclin E, and BAF250a. The genetic etiology of clear cell ECs resembles that of serous ECs, but it remains relatively poorly defined. A detailed discussion of the characteristic patterns of genomic alterations that distinguish the three major histotypes of endometrial cancer is reviewed herein.Keywords: endometrial, cancer, genomics, genetics, sporadic
Sperm protein 17 is highly expressed in endometrial and cervical cancers
Fang-qiu Li, Qun Liu, Yan-ling Han, Bo Wu, Hong-lin Yin
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-429
Abstract: The monoclonal antibodies against human Sp17 were produced as reagents for the analysis and immunohistochemistry was used to study two major kinds of paraffin-embedded gynecological cancer specimens, including 50 cases of endometrial cancer (44 adenous and 6 adenosquamous) and 31 cases of cervical cancer (15 adenous and 16 squamous). Normal peripheral endometrial and cervical tissues were used as controls.Sp17 was found in 66% (33/50) of the patients with endometrial cancer and 61% (19/31) of those with cervical cancer. Its expression was found in a heterogeneous pattern in the cancer tissues. The expression was not correlated with the histological subtype and grade of malignancy, but the staining patterns were different in endometrial and cervical cancers. The hyperplastic glands were positive for Sp17 in the normal peripheral endometrial and cervical tissues in 10% (8/81) of the patients.Sp17 is highly expressed in human endometrial and cervical cancers in a heterogeneous pattern. Although the expression frequency of Sp17 is not correlated with the histological subtype, the staining pattern may help to define endometrial and cervical cancers. Sp17 targeted immunotherapy of tumors needs more accurate validation.Endometrial cancer and cervical cancer are two of the most common malignancies among females globally [1]. Some of them have a poor prognosis due to their chemoresistance and early metastasis. No specific molecular markers are currently available for the early diagnosis and immunotherapy of these aggressive malignancies [2]. Therefore, there is an urgent need to identify tumor antigens associated with chemoresistance and early metastasis which can then be used as suitable targets for immunotherapy.The immunogenic protein, Sperm protein 17 (Sp17), is a member of the cancer testis antigen (CTA) family and has been extensively characterized [3-12]. Sp17 is a highly conserved mammalian protein in the testis and spermatozoa of humans and animals including rabbits
Endometrial Glandular Dysplasia (EmGD): morphologically and biologically distinctive putative precursor lesions of Type II endometrial cancers
Oluwole Fadare, Wenxin Zheng
Diagnostic Pathology , 2008, DOI: 10.1186/1746-1596-3-6
Abstract: Endometrial cancers are the most frequently diagnosed malignancies of the female genital tract in the United States, with 39,080 new cases projected for 2007 [1]. Since 1983, two broad clinicopathologic subtypes of endometrial carcinomas have been recognized [2]. This conceptual classification has largely been supported by subsequent molecular-cytogenetic data, which has facilitated the acceptance of the so-called dualistic model of endometrial carcinogenesis [3-8]. Type I cancers, the prototype of which is the endometrioid histotype, occur in comparatively younger age group [3-8], appear to be related to unopposed estrogen stimulation [9-14], frequently express the estrogen and progesterone receptors [7,13,14], arise in a background of glandular hyperplasia [5,7,13,14], and has a relatively favorable prognostic profile [15]. Genetic alterations in Type 1 cancers include PTEN inactivation [16-19], beta-catenin (CTNNB1) mutations [17], and less frequently, microsatellite instability (related to inactivation of the MLH1 gene) [20,21], and activational mutations of the K-ras gene [22]. Type II cancers, the prototype of which is the endometrial serous carcinoma (ESC), and which was previously termed uterine papillary serous carcinoma (UPSC), typically occur in an older age group [3-8], frequently arise in a background of inactive or resting endometrium [3-8], and display a low frequency of expression of hormonal receptors [13,14,23,24]. Type II cancers also display frequent mutation and overexpression of the p53 [24-26] and HER2/neu [27,28] genes and proteins respectively, and have a comparatively poor prognosis independent of other factors [29-32]. This model has provided a valuable framework for the study of various aspects of endometrial carcinogenesis and for the potential development of therapeutic modalities that are pathway specific. Nonetheless, approximately 7400 deaths attributable to uterine corpus malignancies are projected for 2007 [1]. This relatively high
Prevalence of Lynch Syndrome among Patients with Newly Diagnosed Endometrial Cancers  [PDF]
Cecilia Egoavil, Cristina Alenda, Adela Castillejo, Artemio Paya, Gloria Peiro, Ana-Beatriz Sánchez-Heras, Maria-Isabel Castillejo, Estefanía Rojas, Víctor-Manuel Barberá, Sonia Cigüenza, Jose-Antonio Lopez, Oscar Pi?ero, Maria-Jose Román, Juan-Carlos Martínez-Escoriza, Carla Guarinos, Lucia Perez-Carbonell, Francisco-Ignacio Aranda, Jose-Luis Soto
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079737
Abstract: Background Lynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. The identification of endometrial cancer (EC) patients with LS has the potential to influence life-saving interventions. We aimed to study the prevalence of LS among EC patients in our population. Methods Universal screening for LS was applied for a consecutive series EC. Tumor testing using microsatellite instability (MSI), immunohistochemistry (IHC) for mismatch-repair (MMR) protein expression and MLH1-methylation analysis, when required, was used to select LS-suspicious cases. Sequencing of corresponding MMR genes was performed. Results One hundred and seventy-three EC (average age, 63 years) were screened. Sixty-one patients (35%) had abnormal IHC or MSI results. After MLH1 methylation analysis, 27 cases were considered suspicious of LS. From these, 22 were contacted and referred for genetic counseling. Nineteen pursued genetic testing and eight were diagnosed of LS. Mutations were more frequent in younger patients (<50 yrs). Three cases had either intact IHC or MSS and reinforce the need of implement the EC screening with both techniques. Conclusion The prevalence of LS among EC patients was 4.6% (8/173); with a predictive frequency of 6.6% in the Spanish population. Universal screening of EC for LS is recommended.
Integrated Genomic Analysis of the 8q24 Amplification in Endometrial Cancers Identifies ATAD2 as Essential to MYC-Dependent Cancers  [PDF]
Maria B. Raeder, Even Birkeland, Jone Trovik, Camilla Krakstad, Shyemaa Shehata, Steven Schumacher, Travis I. Zack, Antje Krohn, Henrica MJ. Werner, Susan E. Moody, Elisabeth Wik, Ingunn M. Stefansson, Frederik Holst, Anne M. Oyan, Pablo Tamayo, Jill P. Mesirov, Karl H. Kalland, Lars A. Akslen, Ronald Simon, Rameen Beroukhim, Helga B. Salvesen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054873
Abstract: Chromosome 8q24 is the most commonly amplified region across multiple cancer types, and the typical length of the amplification suggests that it may target additional genes to MYC. To explore the roles of the genes most frequently included in 8q24 amplifications, we analyzed the relation between copy number alterations and gene expression in three sets of endometrial cancers (N = 252); and in glioblastoma, ovarian, and breast cancers profiled by TCGA. Among the genes neighbouring MYC, expression of the bromodomain-containing gene ATAD2 was the most associated with amplification. Bromodomain-containing genes have been implicated as mediators of MYC transcriptional function, and indeed ATAD2 expression was more closely associated with expression of genes known to be upregulated by MYC than was MYC itself. Amplifications of 8q24, expression of genes downstream from MYC, and overexpression of ATAD2 predicted poor outcome and increased from primary to metastatic lesions. Knockdown of ATAD2 and MYC in seven endometrial and 21 breast cancer cell lines demonstrated that cell lines that were dependent on MYC also depended upon ATAD2. These same cell lines were also the most sensitive to the histone deacetylase (HDAC) inhibitor Trichostatin-A, consistent with prior studies identifying bromodomain-containing proteins as targets of inhibition by HDAC inhibitors. Our data indicate high ATAD2 expression is a marker of aggressive endometrial cancers, and suggest specific inhibitors of ATAD2 may have therapeutic utility in these and other MYC-dependent cancers.
Differential Analysis of Ovarian and Endometrial Cancers Identifies a Methylator Phenotype  [PDF]
Diana L. Kolbe, Julie A. DeLoia, Patricia Porter-Gill, Mary Strange, Hanna M. Petrykowska, Alfred Guirguis, Thomas C. Krivak, Lawrence C. Brody, Laura Elnitski
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032941
Abstract: Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, >1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid ovarian tumors indicates that intervention strategies could be developed to specifically address subtypes of epithelial ovarian cancer.
Expression of oestrogen receptors, ERα, ERβ, and ERβ variants, in endometrial cancers and evidence that prostaglandin F may play a role in regulating expression of ERα
Frances Collins, Sheila MacPherson, Pamela Brown, Vincent Bombail, Alistair RW Williams, Richard A Anderson, Henry N Jabbour, Philippa TK Saunders
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-330
Abstract: We compared expression of ERs, progesterone receptor (PR) and cyclooxygenase-2 (COX-2) in stage 1 endometrial adenocarcinomas graded as well (G1), moderately (G2) or poorly (G3) differentiated (n ≥ 10 each group) using qRTPCR, single and double immunohistochemistry. We used endometrial adenocarcinoma cell lines to investigate the impact of PGF2α on expression of ERs and PR.Full length ERβ (ERβ1) and two ERβ variants (ERβ2, ERβ5) were expressed in endometrial cancers regardless of grade and the proteins were immunolocalised to the nuclei of cells in both epithelial and stromal compartments. Immunoexpression of COX-2 was most intense in cells that were ERαneg/low. Expression of PR in endometrial adenocarcinoma (Ishikawa) cell lines and tissues broadly paralleled that of ERα. Treatment of adenocarcinoma cells with PGF2α reduced expression of ERα but had no impact on ERβ1. Cells incubated with PGF2α were unable to increase expression of PR mRNA when they were incubated with E2.We have demonstrated that ERβ5 protein is expressed in stage 1 endometrial adenocarcinomas. Expression of three ERβ variants, including the full-length protein is not grade-dependent and most cells in poorly differentiated cancers are ERβpos/ERαneg. We found evidence of a link between COX-2, its product PGF2α, and expression of ERα and PR that sheds new light on the cross talk between steroid and PG signalling pathways in this disease.Endometrial cancer is the most common gynaecological malignancy and accounts for 5% of cancers in women http://info.cancerresearchuk.org/cancerstats/ webcite. The majority of endometrial cancers occur in post-menopausal women and 80% of patients are diagnosed when the tumour is confined to the uterus (stage 1 disease). Many of the established risk factors for developing endometrial cancer are associated with excess exposure to oestrogen unopposed by progesterone. For example, several studies have reported that use of oestrogen-only hormone replacement therapy (HRT) i
Prevalence of Colorectal Polyps Among Women with Ovarian and Endometrial Cancers Admitted in Firoozgar, Akbarabadi and Rasol Akram Hospitals During 2010- 2011: A Brief Report
S Jafari,S Khaleghi,A Basi,T Ramim
Tehran University Medical Journal , 2012,
Abstract: Background: Patients with endometrial or ovarian cancer have an increased risk for breast or colon cancer. The aim of this study was to assess the individual and age-related characteristics of patients with a combination of these malignancies. Methods: In this retrospective descriptive study, we reviewed the medical records of 100 patients admitted for endometrial or ovarian cancer in Rasol Akram, Akbarabadi and Firozgar educational Hospitals in Tehran, Iran, during 2010- 2011. Colon polyps were evaluated by immunohistochemistry assay. Results: The mean age, weight and BMI of the patients were 50.21, 65.9 and 26.07, respectively. Among 100 cases participating in this study, five (5%) patients had colon polyps. All the five cases with colon polyp had positive familial histories of ovarian cancer. Conclusion: With considering the low prevalence of colorectal polyps among women with ovarian and endometrial cancers, patient's follow-up for screening test is not recommended.
Sequencing of Candidate Chromosome Instability Genes in Endometrial Cancers Reveals Somatic Mutations in ESCO1, CHTF18, and MRE11A  [PDF]
Jessica C. Price, Lana M. Pollock, Meghan L. Rudd, Sarah K. Fogoros, Hassan Mohamed, Christin L. Hanigan, Matthieu Le Gallo, NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program, Suiyuan Zhang, Pedro Cruz, Praveen F. Cherukuri, Nancy F. Hansen, Kirk J. McManus, Andrew K. Godwin, Dennis C. Sgroi, James C. Mullikin, Maria J. Merino, Philip Hieter, Daphne W. Bell
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063313
Abstract: Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromosome instability in endometrial cancer are poorly understood. In the present study, we used Sanger sequencing to search for nucleotide variants in the coding exons and splice junctions of 21 candidate chromosome instability genes, including 19 genes implicated in sister chromatid cohesion, from 24 primary, microsatellite-stable NEECs. Somatic mutations were verified by sequencing matched normal DNAs. We subsequently resequenced mutated genes from 41 additional NEECs as well as 42 endometrioid ECs (EECs). We uncovered nonsynonymous somatic mutations in ESCO1, CHTF18, and MRE11A in, respectively, 3.7% (4 of 107), 1.9% (2 of 107), and 1.9% (2 of 107) of endometrial tumors. Overall, 7.7% (5 of 65) of NEECs and 2.4% (1 of 42) of EECs had somatically mutated one or more of the three genes. A subset of mutations are predicted to impact protein function. The co-occurrence of somatic mutations in ESCO1 and CHTF18 was statistically significant (P = 0.0011, two-tailed Fisher's exact test). This is the first report of somatic mutations within ESCO1 and CHTF18 in endometrial tumors and of MRE11A mutations in microsatellite-stable endometrial tumors. Our findings warrant future studies to determine whether these mutations are driver events that contribute to the pathogenesis of endometrial cancer.
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