Endometrial cancers exhibit a different mechanism of tumorigenesis and progression depending on histopathological and clinical types. The most frequently altered gene in estrogen-dependent endometrioid endometrial carcinoma tumors is PTEN. Microsatellite instability is another important genetic event in this type of tumor. In contrast, p53 mutations or Her2/neu overexpression are more frequent in non-endometrioid tumors. On the other hand, it is possible that the clear cell type may arise from a unique pathway which appears similar to the ovarian clear cell carcinoma. K-ras mutations are detected in approximately 15%–30% of endometrioid carcinomas, are unrelated to the existence of endometrial hyperplasia. A -catenin mutation was detected in about 20% of endometrioid carcinomas, but is rare in serous carcinoma. Telomere shortening is another important type of genomic instability observed in endometrial cancer. Only non-endometrioid endometrial carcinoma tumors were significantly associated with critical telomere shortening in the adjacent morphologically normal epithelium. Lynch syndrome, which is an autosomal dominantly inherited disorder of cancer susceptibility and is characterized by a MSH2/MSH6 protein complex deficiency, is associated with the development of non-endometrioid carcinomas. 1. Introduction Endometrial cancer is the most common cancer of the female reproductive tract with 150,000 new cases diagnosed annually worldwide. Approximately 90% of endometrial cancers are sporadic, and the remaining 10% are hereditary. Bokhman have generally categorized endometrial cancer into two broad groups of tumors using both clinical and histopathological variables: estrogen-dependent endometrioid endometrial carcinomas (EECs), or type I, and non-endometrioid endometrial carcinomas (NEECs), or type II tumors (Table 1) [1]. It should be noted that this model is not strict, and only a minority of endometrial cancer may exhibit shared characteristics. For example, mixed serous and endometrioid tumors are being increasingly recognized. Approximately 70% to 80% of new cases are classified as EECs, and other 10% to 20% are designated as NEEC tumors [1]. EECs are strongly associated with the estrogen-related pathway and arise in association with unopposed estrogen stimulation [2]. In contrast, NEECs are unrelated to the estrogen pathways and arise in the background of atrophic endometrium [3]. EECs typically occur in premenopausal and younger postmenopausal women and are usually low-grade and have a favorable outcome, whereas NEECs occur in older postmenopausal
N. Potischman, R. N. Hoover, L. A. Brinton, et al., “Case-control study of endogenous steroid hormones and endometrial cancer,” Journal of the National Cancer Institute, vol. 88, no. 16, pp. 1127–1135, 1996.
M. E. Sherman, M. E. Bur, and R. J. Kurman, “p53 In endometrial cancer and its putative precursors: evidence for diverse pathways of tumorigenesis,” Human Pathology, vol. 26, no. 11, pp. 1268–1274, 1995.
H. Sasaki, H. Nishii, H. Takahashi, et al., “Mutation of the Ki-ras protooncogene in human endometrial hyperplasia and carcinoma,” Cancer Research, vol. 53, no. 8, pp. 1906–1910, 1993.
B. D. Duggan, J. C. Felix, L. I. Muderspach, J.-L. Tsao, and D. K. Shibata, “Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma,” Cancer Research, vol. 54, no. 6, pp. 1604–1607, 1994.
A. Doll, M. Abal, M. Rigau, et al., “Novel molecular profiles of endometrial cancer-new light through old windows,” Journal of Steroid Biochemistry and Molecular Biology, vol. 108, no. 3–5, pp. 221–229, 2008.
A. Koul, R. Willén, P.-O. Bendahl, M. Nilbert, and A. Borg, “Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis,” Cancer, vol. 94, no. 9, pp. 2369–2379, 2002.
M. Esteller, A. García, J. M. Martínez-Palones, J. Xercavins, and J. Reventós, “The clinicopathological significance of K-RAS point mutation and gene amplification in endometrial cancer,” European Journal of Cancer, vol. 33, no. 10, pp. 1572–1577, 1997.
A. Semczuk, H. Berbe？, M. Kostuch, M. Cybulski, J. Wojcierowski, and W. Baranowski, “K-ras gene point mutations in human endometrial carcinomas: correlation with clinicopathological features and patients' outcome,” Journal of Cancer Research and Clinical Oncology, vol. 124, no. 12, pp. 695–700, 1998.
Y.-Z. Feng, T. Shiozawa, T. Miyamoto, et al., “BRAF mutation in endometrial carcinoma and hyperplasia: correlation with KRAS and p53 mutations and mismatch repair protein expression,” Clinical Cancer Research, vol. 11, no. 17, pp. 6133–6138, 2005.
H. B. Salvesen, R. Kumar, I. Stefansson, et al., “Low frequency of BRAF and CDKN2A mutations in endometrial cancer,” International Journal of Cancer, vol. 115, no. 6, pp. 930–934, 2005.
M. Kawaguchi, M. Yanokura, K. Banno, et al., “Analysis of a correlation between the BRAF V600E mutation and abnormal DNA mismatch repair in patients with sporadic endometrial cancer,” International Journal of Oncology, vol. 34, no. 6, pp. 1541–1547, 2009.
Y. Mizumoto, S. Kyo, N. Mori, et al., “Activation of ERK1/2 occurs independently of KRAS or BRAF status in endometrial cancer and is associated with favorable prognosis,” Cancer Science, vol. 98, no. 5, pp. 652–658, 2007.
O. B. Ioffe, J. C. Papadimitriou, and C. B. Drachenberg, “Correlation of proliferation indices, apoptosis, and related oncogene expression (bcl-2 and c-erbB-2) and p53 in proliferative, hyperplastic, and malignant endometrium,” Human Pathology, vol. 29, no. 10, pp. 1150–1159, 1998.
J. A. Williams Jr., Z.-R. Wang, R. S. Parrish, L. J. Hazlett, S. T. Smith, and S. R. Young, “Fluorescence in situ hybridization analysis of HER-2/neu, c-myc, and p53 in endometrial cancer,” Experimental and Molecular Pathology, vol. 67, no. 3, pp. 135–143, 1999.
B. M. Slomovitz, R. R. Broaddus, T. W. Burke, et al., “Her-2/neu overexpression and amplification in uterine papillary serous carcinoma,” Journal of Clinical Oncology, vol. 22, no. 15, pp. 3126–3132, 2004.
G. Moreno-Bueno, D. Hardisson, C. Sánchez, et al., “Abnormalities of the APC/ -catenin pathway in endometrial cancer,” Oncogene, vol. 21, no. 52, pp. 7981–7990, 2002.
H. Nei, T. Saito, H. Yamasaki, H. Mizumoto, E. Ito, and R. Kudo, “Nuclear localization of -catenin in normal and carcinogenic endometrium,” Molecular Carcinogenesis, vol. 25, no. 3, pp. 207–218, 1999.
K. Shoji, K. Oda, S. Nakagawa, et al., “The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas,” British Journal of Cancer, vol. 101, no. 1, pp. 145–148, 2009.
A. Dutt, H. B. Salvesen, H. Greulich, W. R. Sellers, R. Beroukhim, and M. Meyerson, “Somatic mutations are present in all members of the AKT family in endometrial carcinoma,” British Journal of Cancer, vol. 101, no. 7, pp. 1218–1219, 2009.
S. A. Byron, M. G. Gartside, C. L. Wellens, et al., “Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation,” Cancer Research, vol. 68, no. 17, pp. 6902–6907, 2008.
G. Soufla, S. Sifakis, and D. A. Spandidos, “FGF2 transcript levels are positively correlated with EGF and IGF-1 in the malignant endometrium,” Cancer Letters, vol. 259, no. 2, pp. 146–155, 2008.
G. L. Mutter, M.-C. Lin, J. T. Fitzgerald, et al., “Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers,” Journal of the National Cancer Institute, vol. 92, no. 11, pp. 924–930, 2000.
K. Kurose, X.-P. Zhou, T. Araki, S. A. Cannistra, E. R. Maher, and C. Eng, “Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas,” American Journal of Pathology, vol. 158, no. 6, pp. 2097–2106, 2001.
M. C. Boruban, K. Altundag, G. S. Kilic, and J. Blankstein, “From endometrial hyperplasia to endometrial cancer: insight into the biology and possible medical preventive measures,” European Journal of Cancer Prevention, vol. 17, no. 2, pp. 133–138, 2008.
G. L. Maxwell, J. I. Risinger, C. Gumbs, et al., “Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias,” Cancer Research, vol. 58, no. 12, pp. 2500–2503, 1998.
N. Bansal, V. Yendluri, and R. M. Wenham, “The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies,” Cancer Control, vol. 16, no. 1, pp. 8–13, 2009.
H. B. Salvesen, N. MacDonald, A. Ryan, et al., “PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma,” International Journal of Cancer, vol. 91, no. 1, pp. 22–26, 2001.
T. H. Kim, J. Wang, K. Y. Lee, et al., “The synergistic effect of conditional Pten loss and oncogenic K-ras mutation on endometrial cancer development occurs via decreased progesterone receptor action,” Journal of Oncology, vol. 2010, Article ID 139087, 9 pages, 2010.
T. Kaku, T. Kamura, T. Hirakawa, et al., “Endometrial carcinoma associated with hyperplasia—immunohistochemical study of angiogenesis and p53 expression,” Gynecologic Oncology, vol. 72, no. 1, pp. 51–55, 1999.
H. Tashiro, C. Isacson, R. Levine, R. J. Kurman, K. R. Cho, and L. Hedrick, “p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis,” American Journal of Pathology, vol. 150, no. 1, pp. 177–185, 1997.
E.-J. Lee, T.-J. Kim, D. S. Kim, et al., “p53 alteration independently predicts poor outcomes in patients with endometrial cancer: a clinicopathologic study of 131 cases and literature review,” Gynecologic Oncology, vol. 116, no. 3, pp. 533–538, 2010.
S. F. Lax, B. Kendall, H. Tashiro, R. J. C. Slebos, and L. H. Ellenson, “The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways,” Cancer, vol. 88, no. 4, pp. 814–824, 2000.
S. F. Lax, E. S. Pizer, B. M. Ronnett, and R. J. Kurman, “Clear cell carcinoma of the endometrium is characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor expression,” Human Pathology, vol. 29, no. 6, pp. 551–558, 1998.
T. Okuda, J. Otsuka, A. Sekizawa, et al., “p53 mutations and overexpression affect prognosis of ovarian endometrioid cancer but not clear cell cancer,” Gynecologic Oncology, vol. 88, no. 3, pp. 318–325, 2003.
K. K. Zorn, T. Bonome, L. Gangi, et al., “Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer,” Clinical Cancer Research, vol. 11, no. 18, pp. 6422–6430, 2005.
H.-J. An, S. Logani, C. Isacson, and L. H. Ellenson, “Molecular characterization of uterine clear cell carcinoma,” Modern Pathology, vol. 17, no. 5, pp. 530–537, 2004.
P. Rosenberg, S. Wingren, E. Simonsen, O. Stàl, B. Risberg, and B. Nordenskj？ld, “Flow cytometric measurements of DNA index and S-phase on paraffin-embedded early stage endometrial cancer: an important prognostic indicator,” Gynecologic Oncology, vol. 35, no. 1, pp. 50–54, 1989.
B. Sorbe, B. Risberg, and B. Frankendal, “DNA ploidy, morphometry, and nuclear grade as prognostic factors in endometrial carcinoma,” Gynecologic Oncology, vol. 38, no. 1, pp. 22–27, 1990.
E. M. Swisher, S. Peiffer-Schneider, D. G. Mutch, et al., “Differences in patterns of TP53 and KRAS2 mutations in a large series of endometrial carcinomas with or without microsatellite instability,” Cancer, vol. 85, no. 1, pp. 119–126, 1999.
E. A. Akbay, C. M. Contreras, S. A. Perera, et al., “Differential roles of telomere attrition in type I and II endometrial carcinogenesis,” American Journal of Pathology, vol. 173, no. 2, pp. 536–544, 2008.
W. Yue, R. J. Santen, J.-P. Wang, et al., “Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis,” Journal of Steroid Biochemistry and Molecular Biology, vol. 86, no. 3–5, pp. 477–486, 2003.
K. A. Ashton, A. Proietto, G. Otton, et al., “Estrogen receptor polymorphisms and the risk of endometrial cancer,” BJOG: An International Journal of Obstetrics and Gynaecology, vol. 116, no. 8, pp. 1053–1061, 2009.
F. J. Gonzalez and H. V. Gelboin, “Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins,” Drug Metabolism Reviews, vol. 26, no. 1-2, pp. 165–183, 1994.
F. P. Guengerich and T. Shimada, “Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes,” Chemical Research in Toxicology, vol. 4, no. 4, pp. 391–407, 1991.
S. Saini, H. Hirata, S. Majid, and R. Dahiya, “Functional significance of cytochrome P450 1B1 in endometrial carcinogenesis,” Cancer Research, vol. 69, no. 17, pp. 7038–7045, 2009.
Y. Wang, P. Hanifi-Moghaddam, E. E. Hanekamp, et al., “Progesterone inhibition of Wnt/ -catenin signaling in normal endometrium and endometrial cancer,” Clinical Cancer Research, vol. 15, no. 18, pp. 5784–5793, 2009.
J. J. Koornstra, M. J. Mourits, R. H. Sijmons, A. M. Leliveld, H. Hollema, and J. H. Kleibeuker, “Management of extracolonic tumours in patients with Lynch syndrome,” The Lancet Oncology, vol. 10, no. 4, pp. 400–408, 2009.
P. Peltom？ki, H. F. A. Vasen, M.-L. Bisgaard, et al., “Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer,” Gastroenterology, vol. 113, no. 4, pp. 1146–1158, 1997.
G. Marra and C. R. Boland, “Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives,” Journal of the National Cancer Institute, vol. 87, no. 15, pp. 1114–1125, 1995.
Y. R. Parc, K. C. Halling, L. J. Burgart, et al., “Microsatellite instability and hMLH1/hMSH2 expression in young endometrial carcinoma patients: associations with family history and histopathology,” International Journal of Cancer, vol. 86, no. 1, pp. 60–66, 2000.
P. Schweizer, A.-L. Moisio, S. A. Kuismanen, et al., “Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer,” Cancer Research, vol. 61, no. 7, pp. 2813–2815, 2001.
M. Ollikainen, W. M. Abdel-Rahman, A.-L. Moisio, et al., “Molecular analysis of familial endometrial carcinoma: a manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome?” Journal of Clinical Oncology, vol. 23, no. 21, pp. 4609–4616, 2005.
Y. Hirai, K. Banno, M. Suzuki, et al., “Molecular epidemiological and mutational analysis of DNA mismatch repair (MMR) genes in endometrial cancer patients with HNPCC-associated familial predisposition to cancer,” Cancer Science, vol. 99, no. 9, pp. 1715–1719, 2008.
M. Saegusa, M. Hashimura, T. Kuwata, and I. Okayasu, “Requirement of the Akt/ -catenin pathway for uterine carcinosarcoma genesis, modulating E-cadherin expression through the transactivation of slug,” American Journal of Pathology, vol. 174, no. 6, pp. 2107–2115, 2009.
A. P. Vaidya, N. S. Horowitz, E. Oliva, E. F. Halpern, and L. R. Duska, “Uterine malignant mixed mullerian tumors should not be included in studies of endometrial carcinoma,” Gynecologic Oncology, vol. 103, no. 2, pp. 684–687, 2006.
K. Banno, M. Yanokura, N. Susumu, et al., “Relationship of the aberrant DNA hypermethylation of cancer-related genes with carcinogenesis of endometrial cancer,” Oncology Reports, vol. 16, no. 6, pp. 1189–1196, 2006.
L. Ghabreau, J. P. Roux, A. Niveleau, et al., “Correlation between the DNA global methylation status and progesterone receptor expression in normal endometrium, endometrioid adenocarcinoma and precursors,” Virchows Archiv, vol. 445, no. 2, pp. 129–134, 2004.
P. Mhawech, A. Benz, C. Cerato, et al., “Downregulation of 14-3- in ovary, prostate and endometrial carcinomas is associated with CpG island methylation,” Modern Pathology, vol. 18, no. 3, pp. 340–348, 2005.
B. P. Whitcomb, D. G. Mutch, T.J. Herzog, J. S. Rader, R. K. Gibb, and P. J. Goodfellow, “Frequent HOXA11 and THBS2 promoter methylation, and a methylator phenotype in endometrial adenocarcinoma,” Clinical Cancer Research, vol. 9, no. 6, pp. 2277–2287, 2003.
S. C. Dowdy, B. S. Gostout, V. Shridhar, et al., “Biallelic methylation and silencing of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines,” Gynecologic Oncology, vol. 99, no. 1, pp. 126–134, 2005.
Q. K. Y. Chan, U.-S. Khoo, K. Y. K. Chan, et al., “Promoter methylation and differential expression of -class glutathione S-transferase in endometrial carcinoma,” Journal of Molecular Diagnostics, vol. 7, no. 1, pp. 8–16, 2005.
X. C. Zhou, S. C. Dowdy, K. C. Podratz, and S.-W. Jiang, “Epigenetic considerations for endometrial cancer prevention, diagnosis and treatment,” Gynecologic Oncology, vol. 107, no. 1, pp. 143–153, 2007.
J. I. Risinger, G. L. Maxwell, A. Berchuck, and J. C. Barrett, “Promoter hypermethylation as an epigenetic component in type I and type II endometrial cancers,” Annals of the New York Academy of Sciences, vol. 983, pp. 208–212, 2003.
