The genes responsible for microsatellite instability (MSI) encode proteins involved in DNA mismatch repair (MMR). The ability of cells to repair defects produced during DNA replication is affected when a mutation affects these genes. Hence, cells with defective MMR genes replicate DNA mistakes more frequently than others [8]. These faulty mutations can accumulate in the coding and noncoding DNA sequences, including microsatellites, which are short tandem repeats. Some mononucleotide repeats are located within the coding sequences of important genes (BAX, IGFIIR, hMSH3, hMSH6, MBD4, CHK-1, Caspase-5, ATR, ATM, BML, RAD-50, BCL-10, and Apaf-1) [6].

Seventy five percent of endometrial cancers associated with Lynch syndrome and 25–30 % of sporadic endometrial cancers demonstrate MSI [8]. In sporadic endometrial cancers, MSI is due to MLH-1 promoter hypermethylation and is associated with type I endometrioid cancers rather than type II. The presence of MSI is associated with a higher histological grade [6]. In Lynch syndrome, MSI arises due to mutations arising in MSH2, MH6, MLH1, or PMS2.

PTEN is a tumor suppressor gene, which has important functions in the regulation of cell cycle and apoptosis [9, 10]. This gene is located on chromosome 10q23 and encodes for a protein – phosphatase and tensin homolog (PTEN) – with tyrosine kinase function. The PTEN gene product regulates many key processes in cell such as proliferation, adhesion, migration, and apoptosis and is also a suppressor of tumor growth [11]. PTEN also exerts its effect on cell survival and proliferation through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway [12]. It inhibits PI3K-Akt pathway inducing apoptosis and/or cell cycle arrest [12]. Hence, loss of PTEN function causes aberrant cell proliferation and escape from apoptosis.

The expression of PTEN in the endometrium is controlled by estrogen and progesterone and is expressed more in the proliferative phase than in the secretory [12]. PTEN gene inactivation can occur by point mutation, promoter hypermethylation, or deletion (loss of heterozygosity (LOH)) at 10q23 [6]. PTEN inactivation is seen in 60–80 % of endometrioid cancers and in only less than 10 % of non-endometrioid endometrial cancers [12–15]. The authors have shown loss of PTEN expression in endometrial hyperplasia with and without atypia, and hence, it is thought to play an important role in endometrial cancer tumorigenesis [16]. Altered PTEN expression has been reported in up to 55 % of precancerous lesions of the endometrium, and this is thought to be initiated in response to known hormonal risk factors. Progesterone has shown to promote involution of PTEN-mutated tumor cells [13]. PTEN mutations can coexist with MSI with 60–86 % of MSI-positive endometrial cancers showing PTEN mutations [6]. Data regarding the prognostic significance of PTEN mutations are controversial [17], but Salveston et al. showed correlation between PTEN mutations, low FIGO stages, and favorable prognosis [18]. In this study patients with PTEN mutations had better 5-year survival compared with those with no mutations. PTEN-deficient cells are sensitive to mammalian target of rapamycin (mTOR) inhibitors in vitro since loss of PTEN leads to activation of Akt which upregulates mTOR activity [19]. mTOR inhibitor temsirolimus showed a response rate of 26 % in endometrial cancer patients [20].

This pathway plays an important role in tumorigenesis. Mutations in KRAS proto-oncogene is not present in the normal endometrium but is seen in 6–16 % of atypical hyperplasia and 10–30 % of endometrial carcinomas [13, 21]. It has been shown that as the endometrium changes from normal to varying degrees of hyperplasia, there is an increase in KRAS point mutations [22]. Increased frequency of KRAS mutations is reported in endometrial cancers associated with MSI [23]. BRAF, another member of the RAS-RAF-MEK-ERK pathway, is mutated very infrequently in endometrial cancer [24]. Activated RAS is associated with enhanced cell proliferation, transformation, and cell survival. RAS effectors like RASSF1A (RAS association domain family member 1) are thought to have an inhibitory signal, which needs to be inactivated during tumorigenesis [6]. The increased activity of the RAS-RAF-MEK-ERK pathway can also be due to RASSF1A inactivation by promoter hypermethylation [25].

PI3K (phosphatidylinositol 3-kinase) is a heterodimeric enzyme with a catalytic (p110) and regulatory (p85) subunit. The PIK3CA gene codes the p110α catalytic subunit of this enzyme, which is located on chromosome 3q26.32 [6]. Mutations affecting this subunit have been implicated in many malignancies and may contribute to the alteration of PI3K/AKT signaling pathway in endometrial cancer [13]. Mutations affecting the PIK3CA gene are located mainly in the helical (exon 9) and kinase (exon 20) domains, but mutations can also occur in exons1–7 [6]. In 24–39 % of endometrial cancers, PIK3CA mutations occur, and they coexist frequently with PTEN mutations [26]. PIK3CA mutations affecting exon 20 have been associated with high histological grade and myometrial invasion. Though initially described in endometrioid carcinomas, PIK3CA mutations can also occur in non-endometrioid endometrial carcinomas and mixed tumors. Mutation affecting the p85a inhibitory subunit of PI3K has also been detected in 43 % of endometrioid carcinomas and 12 % of non-endometrioid cancers [6].

Studies have shown elevation of beta-catenin in several cancers including endometrial carcinoma and atypical endometrial hyperplasia [27, 28]. The increased beta-catenin levels occur due to mutation of the beta-catenin gene (CTNNB1) located in chromosome 3p21. Beta-catenin is a part of the E-cadherin-catenin complex, which has a role in cell differentiation and maintenance of normal tissue architecture. When mutation occurs in the exon gene of CTNNB1, there is stabilization of beta-catenin protein leading to its cytoplasmic and nuclear accumulation. It also forms complexes with the DNA-binding proteins and participates in the signal transduction [6]. These mutations are seen in 14–44 % of endometrial cancer and are independent of the presence of MSI, PTEN, or KRAS mutation. Beta-catenin mutations are distributed homogenously in different areas of the tumors suggesting that they play a role in the early steps of endometrial tumorigenesis [13]. There are controversial data regarding the prognostic significance of beta-catenin, but they probably occur in tumors with good prognosis [6].

Studies have indicated that fibroblast growth factor (FGF) signaling pathway is important in endometrial cancer. FGF receptor (FGFR) is downregulated by a protein SPRY-2 that is found inactivated in endometrial cancer [6]. Inactivation of SPRY-2 causes increased cell proliferation. Almost 20 % of endometrial cancers have reduced SPRY-2 immunoexpression. In 6–12 % of endometrial carcinomas, especially in endometrioid types, somatic mutations affecting the receptor tyrosine kinase FGFR2 have been detected [29]. It is of interest to note that FGFR mutations and PTEN mutations often coexist, whereas FGFR mutations and KRAS mutations are mutually exclusive [6]. FGRF2 receptor antibodies are currently considered as targeted therapy agents in endometrial carcinoma.

TP53 mutations are mainly seen in non-endometrioid endometrial cancers (90 %). 10–20 % of endometrioid cancers (mainly grade 3) also exhibit these mutations [3, 30]. TP53 is a tumor suppressor gene located in chromosome 17 (locus 17p13.1). This gene encodes a phosphoprotein called TP53, which participates in cell cycle regulation, DNA repair systems, and apoptosis [11]. Loss of its normal activity prevents apoptosis and promotes tumor progression [31]. An increase in P53 expression from the normal endometrium to hyperplasia through to endometrial carcinoma has been demonstrated by Horee et al., suggesting a possible role in disease progression [32]. Overexpression of TP53 was found to be correlated with advanced stage, lymph node metastases, and high-grade endometrial cancers [33].

HER2/neu receptor is a membrane-bound tyrosine kinase receptor, which belongs to the epidermal growth factor receptor family. It plays a role in regulating cell growth and differentiation. HER2/neu gene amplification results in overexpression of the receptors resulting in increasing cell proliferation. The amplification of HER2/neu is seen in a wide variety of malignancies including breast, ovarian, and endometrial [34–36]. In endometrial cancers HER2/neu overexpression is associated with reduced disease-free and overall survival [37]. Increased expression of HER2/neu is found in about 30 % of uterine serous cancers and 10–20 % of high-grade endometrioid cancers. Well-differentiated endometrioid cancers rarely exhibit HER2/neu positivity [12, 38]. Trastuzumab is a monoclonal antibody, which has targeted action against the HER2/neu protein and is being used widely in breast cancer patients who are HER2/neu positive. But trials using trastuzumab in advanced or recurrent HER2-positive endometrial cancers have failed to show benefit [39].

E-cadherin is a transmembrane glycoprotein of the cadherin family, which promotes and maintains cell adhesion. Cadherins are tissue specific and are required for the assembly of cells into solid tissues [12]. Epithelial cells express E-cadherin and its levels are reduced in many carcinomas including breast, lung, prostate, and also endometrial [12, 40]. Reduced E-cadherin expression was more seen in type 2 endometrial cancers and also in those carcinomas with advanced stage [41]. Fifty seven percent of type 2 endometrial cancers demonstrated loss of heterozygosity of E-cadherin gene at 16q22.1 compared to 22 % of type 1 carcinomas [6].

P16 tumor suppressor gene is located on chromosome 9p21 and this encodes for a cell cycle regulatory protein. Inactivation of p16 leads to uncontrolled cell growth. P16 inactivation was seen in 45 % of serous carcinomas and some clear cell cancers [42].

EGFR is a transmembrane tyrosine kinase receptor, whose mutation has been identified in many malignancies. EGFR overexpression has also been identified in uterine serous carcinomas [43]. Overexpression of EGFR is associated with advanced stage and poor prognosis [44]. EGFR antagonists include tyrosine kinase inhibitors like gefitinib, erlotinib, and lapatinib and anti-EGFR monoclonal antibody cetuximab[42].