What causes endometrial cancer?

Today, it is not clear why EC occurs. Some risk factors have been identified. A risk factor increases the risk that cancer occurs, but is neither necessary nor sufficient to cause cancer. A risk factor is not a cause in itself.

The most common stage 1 EC is estrogen-related. Low grade EC is associated with atypical endometrial hyperplasia and is generally expressing estrogen and/or progesterone receptors (ER/PR positive). This is why, with a few exceptions, the factors increasing the risk of EC are linked to estrogens-induced proliferation and are therefore either endogenous (obesity, anovulatory cycles, estrogen secreting tumors…) or exogenous estrogen exposure (unopposed hormone replacement therapy, Tamoxifen…). In addition, numerous genomic alterations and activation pathways have also been demonstrated.

Estrogens-induced proliferation

Women with a personal history of breast or ovarian cancer outweigh the risk of developing EC as Tamoxifen is commonly given as treatment for its anti-estrogen activity. Decrease in the risk should be expected, but tamoxifen also has a stimulating effect on the endometrium that can support the development of EC.

Figure 8. The patterns of myometrial invasion.

A. Histological section of an EC grade 1 stage 1B showing the extent of myometrial invasion. B. IGs are composed of single or small groups of glands with irregular contours scattered in the myometrium. C. BF, which has a linear limit between the tumor and the stroma beneath. D. MELF identified at the leading edge of the tumor associated with neutrophils infiltration andmicrocystic glands. E. Adenomyosis-like, composed of groups larger than five glands simulating adenomyosis. E. AM is composed of low cytological grade, regular, rounded, and widely spaced glands with no stromal response.

An estimated 40% of cases are thought to be related to obesity. In obesity, the excess of adipose tissue increases conversion of androstenedione into estrone, an estrogen. Higher levels of estrone in the blood cause less or no ovulation and expose the endometrium to continuously high levels of estrogens. Polycystic ovary syndrome (PCOS), which also causes irregular or no ovulation, is associated with higher rates of EC for the same reasons as obesity. Specifically, obesity, type II diabetes, and insulin resistance are risk factors for Type I EC [52]. Obesity increases the risk for EC by 300–400%.

Estrogen replacement therapy during menopause when not balanced (or "opposed") with progestin is another risk factor. Higher doses or longer periods of estrogen therapy have higher risks of EC. Unopposed estrogen raises an individual's risk of EC by 2–10 fold, depending on weight and length of therapy. However, taking contraceptive pills containing both estrogen and progesterone lower the risk of developing EC.

Having more menstrual cycles in a lifetime increases the risk of developing EC, again for hormonal reasons. A longer period of fertility, either from an early first menstrual period or late menopause, is also a risk factor.

Lynch syndrome or HNPCC, an autosomal dominant genetic disorder that mainly causes colorectal cancer, also causes EC, especially before menopause. Women with Lynch syndrome have a 40–60% risk of developing EC, higher than their risk of developing colorectal (bowel) or ovarian cancer. Carcinogenesis in Lynch syndrome comes from a mutation in MLH1 or MLH2: genes that participate in the process of mismatch repair, which allows a cell to correct mistakes in the DNA. Other genes mutated in Lynch syndrome include MSH2, MSH6, and PMS2, which are also mismatch repair genes. Women with Lynch syndrome represent 5% of EC cases [53]. Depending on the gene mutation, women with Lynch syndrome have different risks of EC. With MLH1 mutations, the risk is 54%; with MSH2, 21%; and with MSH6, 16%

[54].

Genomic alterations

Estrogen-related grade 1 EC is typified by high frequency genomic alterations and several genes signature can be identified (Figure 9). Studies using cDNA microarrays confirm that endometrioid cancer grade 1 and serous EC grade 2 and 3 have distinctively different gene expression profiles.

Increasing genetic damage can be seen in precursor lesions within the endometrioid pathway, beginning with PTEN tumor suppressor gene or PAX2 inactivation in normal-appearing glands (latent precancers), followed by positive hormonal selection and clonal outgrowth as non-atypical hyperplasia. PIK3CA mutations play an active role for transition to atypical endometrial hyperplasia. This stage is characterized by FGFR2, ARID1A (BAF250a), KRAS mutations, and activation of the β-catenin gene (CTNNB1), as well as epigenetic silencing of MLH1 and microsatellite instability to finally result in development of low grade EC.

Although this model is applicable to a high proportion of endometrial carcinomas, not all tumors fit in. In fact, a grey zone exists between the two broad grades, with a significant number of tumors showing overlapping clinical, morphologic, and molecular features (Table 1).

Indeed, the estrogen-independent Grade 2 tumors show loss of heterozygosity at different loci, altered p53, and abnormalities in genes regulating mitotic checkpoints. However, p53 mutations are found in 14 to 20% of endometrioid carcinomas grade 1. This finding suggests that p53 is involved in the progression, but not the initiation, of endometrioid carcinoma.

Moreover, there is an ongoing debate about whether a histologic subset of endometrioid carcinomas (those that are poorly differentiated or have high nuclear grade) should be assigned to the grade 2 group. A supporting study also revealed that MELF glands were usually negative for estrogen and progesterone receptor [49]. The MELF pattern of invasion is histologically very heterogeneous with a majority of IG type glands inside the tumor and toward the uterine cavity while MELF glands is mostly observable in the tumor front at the tumor-myometrium interface and thus are the pattern of invasion. We have previously seen that these MELF glands displayed more transformation compared to other types of invasions. A question then remains:

Figure 9. Molecular changes during endometrial carcinogenesis.

Scheme representing the estrogenic pathway leading to EC grade 1 from normal proliferating endometrium adapted from https://www.memorangapp.com/. It is well characterized that PTEN mutation is the first modification leading to non-atypical hyperplasia which is an excessive thickening of the endometrium with normal glandular epithelium. Several other modification of KRAS mutation and β-catenin activation leads to a precancerous atypical hyperplasia with accumulation of aberrant cells. Further mutations leading to AKT activation trigger endometrial tumorigenesis.

MELF glands should thus be associated to estrogen-related grade 1 endometrioid cancer or estrogen-independent grade 2 serous cancers?

Pathways activation

Our understanding of synergies between multiple independent genetic events that produce EC grade 1 centers upon the PI3K pathway, and its ability when perturbed to activate AKT/PKB signaling pathway, promoting survival and growth in response to extracellular signals. It is estimated that more than 80% of EC have an abnormality in the PI3K pathway.

This pathway is initiated by multiple processes including genomic alterations described before.

PTEN inactivation (50-80% of cases), or constitutive activation of KRAS (10–30%) (Table 1) or PIK3CA (30%) act in concert to accumulate PIP3, which in turn activates AKT by phosphorylation (Figure 10). Once activated, pAKT initiates a cascade of tumorigenic events that includes stimulation of the mTOR pathway, deregulation of cell cycle control, blocking of apoptosis, and prolonged cell survival [1].

Recently, it has been demonstrated that increased signal transducer and activator of transcription (STAT3) pathway, increased expression of midkine (MK) and decreased E-cadherin levels in EC cells may also play important roles in EC tumor transformation/dedifferentiation from latent to invasive cancer [55].

The activated Ras protein interacts with RAF to promote RAF phosphorylation and activate MEK. The activated MEK phosphorylates MAPK, which is also known as ERK. This pathway regulates cell proliferation and differentiation in EC. The signaling cascade is activated by several upstream signaling sources, which include genetic alterations (K-Ras mutation), GFs, cytokines, interleukin, and mitogen [56].

This table has been published in a pertinent paper from Lee et al. and shows the incidence of the principal mutations in both estrogen-related grade 1 and estrogen-independent grade 2 EC [1]. As we can see, several genes signatures are paper from Lee et al. and shows the incidence of the principal mutations in both estrogen-related grade 1and estrogen-independent grade 2 EC [1]. As we can see, several genes signatures are found in both highlighting the histologically complexity of EC.

This table has been published in a pertinent paper from Lee et al. and shows the incidence of the principal mutations in both estrogen-related grade 1and estrogen-independent grade 2 EC [1]. As we can see, several genes signatures are found in both highlighting the histologically complexity of EC.

Following activation of PI3K/AKT and p38 MAPK pathways, the PI3K/AKT and p38 MAPK pathways activates and recruits ETS-1 to the promoters of MMP-9 and MMP-13 to induce these genes. These MMPs in turn promote cell migration and invasion followed by metastasis [57].