Molecular Genetics of Endometrial Cancer

PM14CH14_Bell ARI 8 December 2018 14:11
Annual Review of Pathology: Mechanisms of Disease
Molecular Genetics of
Endometrial Carcinoma
Daphne W. Bell1 and Lora Hedrick Ellenson2
Annu. Rev. Pathol. Mech. Dis. 2019.14:339-367. Downloaded from www.annualreviews.org
1
Cancer Genetics and Comparative Genomics Branch, National Human Genome
Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
Access provided by Cornell University on 08/31/20. For personal use only.
email: belldaph@mail.nih.gov
2
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine/New York
Presbyterian Hospital, New York, New York 10065, USA; email: lora.ellenson@med.cornell.edu
Annu. Rev. Pathol. Mech. Dis. 2019. 14:339–67 Keywords

First published as a Review in Advance on endometrioid, serous, carcinosarcoma, carcinoma, molecular classification,
October 17, 2018
genomic, histopathology
The Annual Review of Pathology: Mechanisms of
Disease is online at pathol.annualreviews.org Abstract
https://doi.org/10.1146/annurev-pathol-020117- Endometrial cancer is the most commonly diagnosed gynecologic malig-
043609
nancy in the United States. Endometrioid endometrial carcinomas consti-
Copyright c 2019 by Annual Reviews. tute approximately 85% of newly diagnosed cases; serous carcinomas rep-
All rights reserved
resent approximately 3–10% of diagnoses; clear cell carcinoma accounts for
<5% of diagnoses; and uterine carcinosarcomas are rare, biphasic tumors.
Longstanding molecular observations implicate PTEN inactivation as a ma-
jor driver of endometrioid carcinomas; TP53 inactivation as a major driver
of most serous carcinomas, some high-grade endometrioid carcinomas, and
many uterine carcinosarcomas; and inactivation of either gene as drivers of
some clear cell carcinomas. In the past decade, targeted gene and exome
sequencing have uncovered additional pathogenic aberrations in each his-
totype. Moreover, an integrated genomic analysis by The Cancer Genome
Atlas (TCGA) resulted in the molecular classification of endometrioid and
serous carcinomas into four distinct subgroups, POLE (ultramutated), mi-
crosatellite instability (hypermutated), copy number low (endometrioid), and
copy number high (serous-like). In this review, we provide an overview of
the major molecular features of the aforementioned histopathological sub-
types and TCGA subgroups and discuss potential prognostic and therapeutic
implications for endometrial carcinoma.
339
1. INTRODUCTION
Endometrial carcinoma is the sixth leading cause of cancer-related death among women in the
United States, causing an estimated 11,350 deaths in 2018 (1). The number of newly diagnosed
endometrial cancers in the United States has been increasing steadily over time. This trend is
expected to continue and is attributed, at least in part, to increasing rates of obesity and an aging
US population, both of which are risk factors for certain endometrial cancers (2). Racial disparities
in survival from uterine cancer also persist, exemplified by a 5-year survival rate of 84% for white
women and 62% for black women (1).
There are three distinct but overlapping dimensions used to categorize endometrial tumors:
pathogenetic, histopathologic, and molecular. In 1983, Bokhman proposed the existence of two
pathogenetic types of endometrial cancer, type I and type II, based on the presence (type I) or
absence or occult presence (type II) of obesity, hyperlipidemia, and signs of hyperestrogenism in
patients (3). Type I tumors generally demonstrated high or moderate degrees of differentiation, su-
perficial invasion of the myometrium, frequent progestogen sensitivity, and favorable prognosis. In
contrast, type II tumors were enriched for poorly differentiated tumors, deep myometrial invasion,
metastasis to pelvic lymph nodes, lower rates of progestogen sensitivity, and relatively unfavorable
prognosis. Histopathologically, endometrial carcinoma can be classified as endometrioid and its
variants (see Section 2.1), mucinous, serous, clear cell, neuroendocrine, mixed, undifferentiated,
or dedifferentiated. Additionally, a small percentage of carcinomas demonstrate mesenchymal dif-
ferentiation and are referred to as carcinosarcoma. Among newly diagnosed cases, approximately
85% or more are endometrioid carcinoma, 3–10% are serous carcinoma, 2–3% are clear cell
carcinoma, and fewer than 2% are carcinosarcoma, with the remainder accounted for by other
histotypes (4).
There is a less than perfect correlation between histopathological subtypes and pathogenetic
types of endometrial cancer (5). However, endometrioid carcinomas are considered prototypical
type I tumors, whereas serous carcinomas are considered prototypical type II tumors. Endometri-
oid and serous carcinomas also have distinguishing molecular features, with loss of PTEN function
being a major driver of endometrioid carcinoma and loss of p53 function driving a majority of
serous carcinomas. Recently, an analysis of endometrioid and serous endometrial carcinomas by
The Cancer Genome Atlas (TCGA) led to the description of four distinct molecular subgroups:
POLE-mutated (ultramutated), microsatellite unstable (hypermutated), copy number low (en-
dometrioid), and copy number high (serous-like) (6). Endometrioid carcinomas populate all four
molecular subgroups, whereas serous carcinomas are almost exclusively in the copy number high
(serous-like) subgroup. This molecular classification provides an alternate lens through which
to view and describe endometrial tumors, while adding significant diagnostic, prognostic, and
therapeutic targets.
In this review, our goal is to provide an overview of the major pathologic and molecular fea-
tures of endometrial carcinoma and carcinosarcoma and to highlight those findings with potential
diagnostic, prognostic, and therapeutic implications to improve the outcomes of women with
endometrial cancer.
2. HISTOPATHOLOGY OF ENDOMETRIAL CARCINOMA

AND PRECURSOR LESIONS
Presently, endometrial carcinoma is classified based on light microscopic features using the World
Health Organization (WHO) classification system, which remains the gold standard in the diag-
nostic arena (see the sidebar titled World Health Organization 2014 Classification of Endometrial
Carcinoma) (7). However, identification of specific molecular genetic alterations has provided
340 Bell · Ellenson

WORLD HEALTH ORGANIZATION 2014 CLASSIFICATION OF ENDOMETRIAL

CARCINOMA
Endometrioid carcinoma, usual type

Endometrioid carcinoma, variant types
Squamous differentiation
Villoglandular
Secretory
Mucinous carcinoma
Serous carcinoma
Neuroendocrine tumors
Low grade
High grade
Mixed-cell adenocarcinoma
Undifferentiated carcinoma
Dedifferentiated carcinoma
supportive diagnostic criteria, as is discussed in this section. In addition, recent next-generation

sequencing studies have offered novel insights into the morphologic variants of endometrial car-
cinoma. As is clear from the WHO classification, there are a relatively large number of histologic
types of endometrial carcinoma. In this review, only the most common types are discussed in detail
and described in the context of the molecular data.
2.1. Endometrioid Carcinoma

Endometrioid carcinoma is the most common type of endometrial carcinoma, accounting for
approximately 85% of cases. The name is derived from the morphologic appearance of the malig-
nant glands, which mimic normal proliferative endometrium. Endometrioid carcinoma is divided
into usual and variant types based on the presence of specific types of cellular differentiation. The
usual type is composed largely of glands that have a complex architectural growth pattern, with
extensive glandular branching and associated papillary patterns not found in normal proliferative
endometrium. The glands consist of cells with elongated or rounded nuclei that are commonly
pseudostratified yet retain the smooth luminal borders seen in proliferative endometrium. The
nuclei are typically low grade, and the presence of high-grade nuclei should suggest the possibility
of nonendometrioid carcinoma (Figure 1). The number of mitotic figures is highly variable. The
presence of squamous, mucinous, and villoglandular differentiation is common in endometrioid
carcinoma, and these constitute the most common morphologic variants. Squamous differentia-
tion occurs in approximately 10–25% of endometrioid carcinomas and is important to recognize,
as sheets of cells with squamous differentiation are not considered to make up a solid growth
pattern for purposes of grading endometrioid carcinoma (see below). Mucinous differentiation is
also quite common, and when it is present in over 50% of the tumor, which is rare, it is classified
as the distinct entity of mucinous carcinoma. Secretory and ciliated differentiation are uncommon
variants and are not discussed.
Endometrioid carcinoma is divided into three architectural grades (1–3) depending on the
percentage of solid growth, as defined by the International Federation of Gynecology and
www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 341

a b
c d
Figure 1
Endometrioid carcinoma grade 1. (a) Hematoxylin and eosin, 200×. (b) MSH2 immunohistochemistry, 200×.
(c) MLH1 immunohistochemistry, 200×. (d ) PMS2 immunohistochemistry, 200×.
Obstetrics (FIGO). Grade 1 tumors are almost exclusively composed of glands, grade 2 tumors
contain 6–50% solid growth, and grade 3 tumors have greater than 50% solid growth. Most en-
dometrioid carcinomas are classified as grade 1 or 2, share epidemiologic and molecular features,
and generally have a favorable prognosis. Grade 3 tumors, however, have a poorer prognosis, and
although they share some molecular alterations with grade 1 and 2 tumors, approximately 50%
demonstrate TP53 mutations, which are rare in the lower-grade tumors (8). Some studies have
suggested that a binary system of grading, combining grade 1 and 2 tumors as low grade and clas-
sifying grade 3 tumors as high grade, would better reflect the biology of endometrioid carcinoma
(9). However, this has not been widely accepted. Interestingly, approximately 20% of grade 3 tu-
mors are in the copy-number-high (serous-like) TCGA subtype, while the vast majority of grade
1 and 2 tumors fall into the other three TCGA subtypes of endometrial carcinoma (discussed in
Section 4).
Complex atypical hyperplasia (CAH, also known as endometrioid intraepithelial neoplasia) has
long been recognized as the precursor of grade 1 and 2, and perhaps some grade 3, endometrioid
carcinomas. It is morphologically defined by the presence of nuclear atypia in endometrial glands
with complex glandular growth patterns, including branching and papillary infoldings similar to
those seen in carcinoma, but without stromal or myometrial invasion. The risk of developing
carcinoma from CAH was demonstrated in a landmark natural history study. It was shown that
approximately 25% of women with CAH develop carcinoma, as compared to only 3% of women
with complex hyperplasia without nuclear atypia (10). As the names imply, the significant difference
between the two entities is the presence of cytologic atypia in CAH. Both of these lesions, like

endometrioid carcinoma, are associated with exposure of the endometrium to unopposed estrogen,
and they are generally thought to represent a continuum of abnormal proliferation. However, it is
clear that the presence of nuclear atypia represents a fundamental change that predisposes women
to the development of carcinoma (11). Unfortunately, there is very poor intra- and interobserver
reproducibility in the identification of nuclear atypia, a limitation of morphologic evaluation with
clear consequences for the reliable recognition of women at risk of developing carcinoma (12).
This uncertainty creates a difficult clinical issue for women of childbearing years who wish to
retain fertility. Objective molecular markers to distinguish complex hyperplasia from CAH and
CAH from carcinoma would provide much-needed diagnostic tools. Studies on relatively small
numbers of cases have suggested some potential molecular alterations that occur in statistically
significant frequencies (e.g., PIK3CA mutations), but larger and more comprehensive molecular
studies are required to identify markers and verify their ability to improve diagnostic accuracy (13).
2.2. Serous Carcinoma

Only 3–10% of endometrial carcinoma is of the serous type, but due to its aggressive behavior, it
causes a disproportionate number of deaths. The signature feature of serous carcinoma is marked
cytological atypia consisting of high-grade nuclei, often with prominent eosinophilic nucleoli and
atypical mitotic figures. Architecturally, serous carcinoma may display papillary and/or glandular
patterns, or more uncommonly, a solid growth pattern. The glandular and papillary growth pat-
terns usually display scalloped luminal borders, which differ from the smooth borders typically
observed in the glands and papillae of endometrioid carcinoma. Although the papillae can be thin
and delicate like the villoglandular variant of endometrioid carcinoma, they are often short and
thick, with associated dense fibrosis. The main distinguishing feature is the marked nuclear atypia
in serous carcinoma, compared to the low-grade nuclei of grade 1 and 2 endometrioid carcinoma
(Figure 2). All serous carcinomas are considered to be high-grade (FIGO grade 3) tumors.
In the early 1990s, mutations in the TP53 gene were identified in approximately 90% of serous
carcinomas of the endometrium, with the majority consisting of missense mutations (14). The
missense mutations were found to correlate with intense, diffuse immunohistochemical staining
for p53; by contrast, a complete lack of staining (null pattern) for p53 was indicative of nonsense
or frameshift mutations. Thus, p53 immunohistochemistry became a widely used diagnostic tool
to support the diagnosis of serous carcinoma in the appropriate setting.
Unlike endometrioid carcinoma, which commonly arises in the setting of unopposed estrogen
exposure via hyperplastic precursor lesions, serous carcinoma most commonly occurs in a back-
ground of endometrial atrophy. The precursor lesion, termed serous endometrial intraepithelial
carcinoma (SEIC), is composed of cells morphologically identical to those of serous carcinoma
but is confined to the epithelial surfaces without evidence of invasion (15). The presence of TP53
mutations in SEIC supports the idea that TP53 mutation is an early driver of serous carcinoma
development. The biologic behavior of SEIC, however, suggests that it may best be considered a
malignancy, as synchronous and metachronous metastases have been identified even in the absence
of invasion in the endometrium or myometrium. Thus, the name minimal serous carcinoma has
been proposed as an alternative to SEIC to emphasize its potential malignant behavior.
2.3. Clear Cell Carcinoma

Clear cell carcinoma is uncommon, accounting for less than 5% of endometrial carcinomas. Clin-
ically, all pure clear cell carcinomas are classified as grade 3 tumors. However, over the years,
many clinicopathological and early molecular studies have suggested that the category of clear

a b
c d
Figure 2
Serous carcinoma. (a) Hematoxylin and eosin, 200×. (b) Estrogen receptor immunohistochemistry, 200×.
(c) p53 immunohistochemistry, 200×. (d ) p16 immunohistochemistry, 200×.
cell carcinoma is heterogeneous. Morphologically, clear cell carcinomas are classically composed
of cells with high-grade nuclei (at least focally) and clear cytoplasm that grow in a number of
architectural patterns, including tubulocystic, papillary, or solid. Paradoxically, not all clear cell
carcinomas have clear cells (some have eosinophilic cytoplasm, i.e., the eosinophilic variant), and
not all carcinomas with clear cells are clear cell carcinomas. Given the array of architectural growth
patterns and the ambiguous cytoplasmic differentiation, the diagnosis of clear cell carcinoma can
be problematic. It has long been recognized that clear cell differentiation can also be seen in both
endometrioid and serous carcinoma. All of these factors have contributed to variability in studies
on the biological behavior, as well as on the pathogenesis, of clear cell carcinoma; however, as
is discussed in Section 3, even pure clear cell carcinoma represents a heterogeneous group of
tumors. Additional molecular studies of larger series with robust clinicopathological correlations
are necessary to shed light on this somewhat enigmatic type of endometrial carcinoma. Immuno-
histochemical analysis is often used clinically, as most cases show a wild-type p53 staining pattern
and are positive for HNF-1β and NapsinA and negative for estrogen receptor and progesterone
receptor (Figure 3) (16, 17). However, approximately 46% of cases show focally strong p53 stain-
ing, supportive of the presence of subclonal TP53 mutations (18). Clear cell carcinoma usually
occurs in older women in association with atrophy and can be found in endometrial polyps, but
exceptions occur. A precursor lesion to clear cell carcinoma has not been identified. The 5-year
survival for women diagnosed with clear cell carcinoma is approximately 50%, but as with serous
carcinoma, women who present with stage I disease have a favorable prognosis.

a b
c d
Figure 3
Clear cell carcinoma. (a) Hematoxylin and eosin, 200×. (b) Estrogen receptor immunohistochemistry, 200×.
(c) p53 immunohistochemistry, 200×. (d ) Napsin immunohistochemistry, 200×.
2.4. Undifferentiated and Dedifferentiated Carcinoma

Undifferentiated carcinoma is a rare entity defined by the WHO as a tumor lacking any evidence
of differentiation and further subclassified as dedifferentiated if it is associated with a sharply de-
marcated area of a low-grade (grade 1 or 2) endometrioid carcinoma (19). The tumor is composed
of sheets of monotonous small- to intermediate-size cells that are discohesive. There are numer-
ous mitotic figures, and the nuclei are often vesicular, with small nucleoli. At low magnification,
undifferentiated carcinoma can resemble a low-grade stromal sarcoma, a small-cell carcinoma, or
lymphoma. On closer view, it lacks the vasculature of stromal sarcoma and the nuclear molding
and salt and pepper chromatin pattern of small-cell carcinoma. The other main entity in the differ-
ential is a grade 3 endometrioid carcinoma, which usually contains at least focal areas of intermixed
glandular differentiation or has features of a nonkeratinizing, poorly differentiated squamous car-
cinoma. In contrast, dedifferentiated carcinomas have a sharp border between the undifferentiated
component and the low-grade endometroid component. In addition, the low-grade component
is most commonly present on the endometrial surface, whereas the undifferentiated component
infiltrates the myometrium. The tumors occur in women across a wide range of ages and are
typically aggressive, with half of patients presenting with metastatic disease. Recent molecular
studies, however, suggest that the tumors are heterogenous. Importantly, some tumors demon-
strate loss of DNA mismatch repair proteins by immunohistochemistry and are associated with
Lynch syndrome.

2.5. Carcinosarcoma
Uterine carcinosarcoma is rare, accounting for less than 2% of all uterine cancer diagnoses (4).
It is a biphasic tumor with both carcinomatous and sarcomatous components. The histology of
each component is variable. The carcinomatous component can be of serous, clear cell, undiffer-
entiated, high-grade endometrioid, or mixed histology, or, less commonly, it can be lower-grade
endometrioid carcinoma (20). The sarcomatous component can be composed of mesenchymal
elements that occur in the uterus (homologous), such as stromal sarcoma or leiomyosarcoma, or
of extrauterine (heterologous) origin, such as rhabdomyosarcoma, chondrosarcoma, or osteosar-
coma (21). The presence of a heterologous component is associated with relatively poor prognosis.
Three main theories (collision, combination, conversion) have been suggested to account for the
biphasic nature of uterine carcinosarcomas (22). The collision theory proposes that the carcinoma
and sarcoma components have independent origins and collide to form a single tumor. The com-
bination theory proposes a single precursor stem cell and subsequent differentiation to give rise
to two histological components. The conversion theory proposes a monoclonal origin and meta-
plastic transition from carcinoma to sarcoma. Separate molecular analyses of paired carcinoma
and sarcoma components support the conversion theory in a majority of uterine carcinosarcomas
(22–25). Carcinosarcoma is included in this review based on convincing molecular and clini-
copathological data supporting the idea that it is a carcinoma with sarcomatous differentiation.
Uterine carcinosarcomas are aggressive cancers that usually present as large, polypoid endome-
trial tumors that often protrude through the cervical os. They metastasize in a similar pattern to
endometrial carcinomas, and the majority of the metastases are composed of the carcinomatous
component.
3. MOLECULAR PATHOGENESIS OF ENDOMETRIAL CARCINOMAS

AND CARCINOSARCOMAS
3.1. Endometrioid Endometrial Carcinomas

The systematic sequencing of endometrioid carcinomas by TCGA identified at least 216 protein-
encoding genes that are either bona fide or putative pathogenic driver genes for this histotype (6).
The most frequently altered genes and pathways identified by TCGA had been established by other
studies as having roles in endometrioid carcinoma. However, TCGA provided deeper insights into
the molecular mechanisms of pathway alterations, identified previously unrecognized driver genes,
and described a new molecular classification of endometrioid carcinoma, as described in more detail
in Section 4. Overall, the endometrioid histotype is characterized by frequent perturbations of the
PI3K–PTEN–AKT–mTOR, RAS–MEK–ERK, and canonical WNT–β-catenin pathways; a high
rate of microsatellite instability (MSI), reflecting mismatch repair (MMR) defects; and a relatively
high incidence of POLE mutations associated with an ultramutated phenotype. The ARID1A
(BAF250A) tumor suppressor gene is also frequently dysregulated in endometrioid carcinoma
(26).
3.1.1. The PI3K–PTEN–AKT–mTOR pathway. Signal transduction via the PI3K–PTEN–

AKT–mTOR pathway regulates cell growth, cell survival, protein synthesis, and metabolism
(Figure 4). Molecular aberrations in this pathway occur in 80–95% of endometrioid carcino-
mas (6, 27, 28). Somatic mutation of the PTEN tumor suppressor, which normally antagonizes
PI3K pathway activation, occurs in 69–80% of endometrioid tumors and is the most common
genomic aberration in this subtype (6, 29). PTEN mutation is an early event in the pathogenesis of

Ligand
Ligand-stimulated
receptor tyrosine EXTRACELLULAR SPACE
kinases
PTEN LKB1 CYTOPLASM

PDK1
PIP2 PIP3
P GRB2
P
P p85α Energy
p110α AKT P
SOS stress
P
RAS AMPK
P
RAF TSC1/2
mTORC2
Rheb- Rheb-
Rheb- complex
MEK1/2 GTP GDP
GTP
mTORC1
P P P
complex
ERK1/2 GSK3β FOXO BAD
4E-BP1 S6K
Cell Cell survival, cell Translation,

proliferation proliferation, metabolism cell growth
Figure 4
The PI3K and RAS–MAPK pathways. Activation of the PI3K pathway ( yellow) is triggered by ligand stimulation of receptor tyrosine
kinases, leading to receptor autophosphorylation (as shown) or to phosphorylation of an adaptor protein bound to the receptor (not
shown). The regulatory subunit (p85α) of PI3K binds to such phosphorylated tyrosine residues, which removes the inhibitory effect of
p85α on the catalytic subunit (p110α) of PI3K. Once activated, PI3K catalyzes the conversion of phosphatidylinositol-4,5-bisphosphate
(PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 recruits and binds to the pleckstrin homology domain containing
proteins AKT and PDK1, bringing these kinases into proximity of one another and facilitating PDK1-induced phosphorylation of
AKT on Threonine 308; full activation of AKT also requires mTORC2-induced phosphorylation of AKT-Serine 473. Once activated,
AKT phosphorylates the TSC2 tumor suppressor, which inhibits the conversion of Rheb-GTP to Rheb-GDP by the TSC1/2 complex,
resulting in Rheb-GTP-mediated activation of the mTORC1 complex (mTOR–RAPTOR–MLST8). Activated mTORC1 results in
increased protein biosynthesis and cell growth via S6K and 4E-BP1. Activation of the PI3K–AKT pathway also promotes cell survival,
proliferation, and/or metabolism via GSK3β, FOXO, and BAD. The PTEN tumor suppressor, a dual-specificity phosphatase,
negatively regulates the PI3K–AKT pathway by converting PIP3 to PIP2. Under conditions of energy stress ( green), the activities of
the LKB1 and AMPK kinases downregulate the mTORC1 complex. Signal transduction via the RAS pathway also occurs in response
to ligand-stimulated receptor tyrosine kinases and is mediated by RAF–MEK–ERK and/or by PI3K. Red circles depict proteins for
which targeted therapies have entered clinical trials in endometrial cancer.
endometrioid carcinoma, since it is present in a relatively large proportion of endometrial hyper-

plasia and CAH (30, 31). Loss of PTEN function in endometrial tumors, via inactivating mutation,
deletion, or loss of protein expression, is associated with elevated levels of phosphorylated AKT
(28).

In addition to PTEN perturbations, somatic mutations in PIK3CA and PIK3R1, which encode
the catalytic (p110α) and regulatory (p85α) subunits of PI3K, are also frequent in endometrioid
carcinoma (40–56% and 20–43%, respectively) (6, 27, 28, 32). Although there are exceptions,
PIK3CA and PIK3R1 mutations tend to co-occur with PTEN alterations, suggesting additive or
synergistic effects (6, 27, 28, 33, 34). In contrast, PIK3CA and PIK3R1 mutations are generally
mutually exclusive, suggesting functional equivalency (6, 27, 28). However, the functional conse-
quences of individual PIK3CA mutations can vary depending on the specific protein domain in
which they occur (35). This phenomenon is particularly relevant to endometrial cancer, which
has a high frequency of PIK3CA mutations in the amino-terminal domains of p110α in addition
to mutations in the C-terminal helical and kinase domains (6, 32). Similar to PIK3CA, the func-
tional consequences of PIK3R1 mutations can also vary according to mutation type and position.
For example, in-frame deletions of PIK3R1 that localize to the iSH2 domain of p85α result in
increased phosphorylation of AKT (27, 28), whereas two N-terminal truncating mutants acti-
vate ERK and JNK2 (36). Collectively, these findings emphasize the translational importance of
understanding the biochemical effects of individual mutations in PI3K (36). The role of PTEN
early in the pathogenesis of endometrioid carcinoma has been confirmed by a number of genet-
ically engineered mouse models, including models that carry heterozygous deletion of Pten or
that have conditional deletion of Pten in the endometrial epithelium. These mice develop CAH
with complete penetrance that progresses to carcinoma as the mice age. Furthermore, conditional
activation of Pik3ca in the setting of Pten deletion results in earlier onset, more aggressive disease
(37, 38).
Other mechanisms by which the PI3K–PTEN–AKT–mTOR pathway is dysregulated in en-
dometrial tumors include inactivation of the TSC2 (Tuberin) and LKB1 (STK11) tumor sup-
pressors (39). Loss of TSC2 or LKB1 protein expression has been reported in 13% and 21% of
endometrioid carcinomas, respectively (39), and dysregulation of LKB1 phosphorylation has also
been observed (39). The idea that LKB1 inactivation is a driver of endometrial cancer is supported
by mouse models in which conditional inactivation of Lkb1 in the endometrium promotes tumori-
genesis (40, 41). Moreover, the conditional deletion of Lkb1 and Pten in the murine endometrium
is cooperative in promoting endometrioid endometrial tumorigenesis (42).
The frequent activation of the PI3K–PTEN–AKT–mTOR pathway in endometrial carci-
noma makes it an attractive therapeutic target in this tumor type. Phase II clinical trials evaluating
the efficacy of mTOR inhibitors, PI3K inhibitors, AKT inhibitors, and dual PI3K–mTOR in-
hibitors for the treatment of endometrial cancer are ongoing, planned, or completed. In addition,
Phase II trials of PARP inhibitors are underway, based on preclinical evidence that PTEN de-
ficiency may be synthetic lethal with PARP inhibition in endometrial cancer (43). Thus far, the
rapamycin analogs temsirolimus (Pfizer Inc.), everolimus (Novartis), and ridaforolimus (ARIAD
Pharmaceuticals), which target mTOR, have demonstrated “modest but reproducible” (44, p. 103)
activity in endometrial cancer when administered as monotherapy (44, 45). Pilaralisib (SAR245408;
XL147; Sanofi/Exelixis), a pan-PI3K inhibitor, demonstrated minimal antitumor activity in a
Phase II single-arm, two-stage study evaluating safety and efficacy in patients with advanced or re-
current endometrial cancer (46). A recent Phase II study of the PI3K inhibitor buparlisib (BKM120;
Novartis) as monotherapy in advanced or recurrent endometrial cancer reported minimal anti-
tumor activity and an unfavorable safety profile (47). A Phase II study of apitolisib (GDC-0980;
Genentech/Roche), a dual PI3K–mTOR inhibitor, in recurrent or persistent endometrial cancer
reported limited drug tolerability (48). In a randomized Phase II trial of the dual PI3K–mTOR
inhibitors PF-04691502 (Pfizer) and gedatolisib (PF-05212384; Pfizer) in recurrent endometrial
cancer (49), PF-04691502 demonstrated unacceptable toxicity, whereas gedatolisib had manage-
able toxicity and single-agent activity (clinical benefit response rate: 40%; 95% CI: 24–57%) (49).

3.1.2. The RAS–RAF–MEK–ERK pathway and fibroblast growth factor receptor 2. The
RAS–RAF–MEK–ERK pathway is a key regulator of cell proliferation, cell survival, and differ-
entiation (Figure 4). The predominant mechanism of RAS–RAF–MEK–ERK pathway activation
in endometrioid carcinoma is KRAS mutation, which occurs in 15–24% of endometrioid tumors
overall, and at a significantly higher frequency among MSI-positive endometrioid carcinomas
(6, 28, 29, 50, 51). Most KRAS-mutated endometrioid carcinomas also have co-occurring alter-
ations in PTEN, PIK3CA, and/or PIK3R1 (6, 27–29, 50). Although there is crosstalk between the
RAS–RAF–MEK–ERK and PI3K–AKT–mTOR pathways (Figure 4), KRAS mutation is associ-
ated with increased phosphorylation of MEK1/2, ERK1/2, and p38MAPK, but not of AKT, in
endometrial carcinoma (28).
Based on preclinical data, KRAS mutation appears to be an imperfect indicator of sensitivity
to MEK inhibitors (28, 52). For example, endometrial cancer cell lines with concomitant KRAS
mutation and PI3K pathway aberrations show variable sensitivities to MEK inhibition, with some
cell lines being sensitive but others insensitive (28, 52). Moreover, sensitivity to MEK inhibition has
also been observed in endometrial cancer cell lines that lack KRAS mutation (28, 52), some of which
have mutated HRAS or NRAS (52). In the clinical setting, a Phase II study of selumetinib (ZD6244;
AstraZeneca), a small-molecule inhibitor of MEK1/2, in patients with recurrent endometrial
cancer showed tolerability but minimal single-agent activity (53). Preclinical studies combining
MEK and PI3K pathway inhibitors have shown synergistic effects in endometrial cancer cell lines
(53–55), and clinical studies assessing such agents as combination therapy are underway.
Activation of the fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinase can
initiate signal transduction through the RAS–MAPK, PI3K, PLCγ, and JAK–STAT pathways
and can regulate cellular processes such as cell survival, growth, proliferation, migration, and an-
giogenesis. FGFR2 is mutated in approximately 10% of endometrioid carcinomas, and at least
84% of such mutations are activating (6, 50, 56, 57). The near mutual exclusivity of FGFR2 and
KRAS mutation in endometrioid carcinomas has led to the suggestion that FGFR2 mutations ac-
tivate the RAS–MAPK pathway in this cellular context (50). As shown using multivariate analysis,
activating FGFR2 mutations in endometrioid carcinoma are significantly associated with adverse
outcomes, specifically, shorter progression-free survival (PFS) (HR 1.903; 95% CI 1.177–3.076;
p = 0.009) and shorter disease-specific survival (HR 2.013; 95% CI 1.096–3.696; p = 0.024),
even among patients with early stage (stage I/II) disease (56). Tyrosine kinase inhibitors that in-
clude FGFR2 as a target have entered clinical trials for endometrial cancer. A Phase II study of
brivanib (BMS-540215; Bristol-Myers Squibb), a small-molecule inhibitor of FGFR and VEGFR,
in unselected endometrial cancer patients with recurrent or persistent disease following cytotoxic
therapy reported a clinical response rate of 18.6% (90% CI 9.6%–31.7%) and 30.2% (90% CI
18.9%–43.9%) PFS at 6 months; rates of 6-month PFS were higher for endometrioid carcinoma
(31.5%) or mixed epithelial subtypes (50%) compared with serous carcinoma (10%) (58). Based on
Gynecologic Oncology Group guidelines, brivanib was considered of interest for further develop-
ment for treatment of endometrial cancer. Dovotinib (TKI258/CHIR258; Oncology Venture) is a
small-molecule inhibitor of multiple receptor tyrosine kinases, including FGFR1–3, VEGFR1–3,
PDGFR-β, FLT3, and c-KIT. A nonrandomized, two-group, two-stage, Phase II study of dovo-
tinib as second-line treatment for advanced or metastatic endometrial cancer concluded that it has
single-agent activity in FGFR2-mutated and FGFR2-nonmutated advanced or metastatic disease
(59). Specifically, PFS at 18 weeks was 31.8% (95% CI 13.9–54.9%) for the FGFR2-mutated
group and 29.0% (95% CI 14.2–48.0%) for the FGFR2-nonmutated group. Clinical benefit
(complete response, partial response, stable disease) was 64% for the FGFR2-mutated group
and 52% for the FGFR2-nonmutated group. A Phase II study of nintedanib (Boehringer Ingel-
heim), a small-molecule inhibitor of FGFR1–3, VEGFR1–3, and PDGFRα, reported a 6-month

event-free survival rate of 21.9% (90% two-sided CI 10.7–37.2%) and an overall response rate of
9.4% (90% two-sided CI 2.6–22.5%) (60).
3.1.3. The canonical WNT–β-catenin pathway. The canonical WNT–β-catenin pathway

regulates a variety of cellular processes, including cell proliferation, cell migration, cell survival,
cell fate, and cell polarity (Figure 5). In endometrioid carcinomas, this pathway is often constitu-
tively activated as a result of gain-of-function mutations in CTNNB1 (β-catenin), which prevent
WNT
Frizzled
LRP5/6 EXTRACELLULAR SPACE
CYTOPLASM
P
DVL DVL
P
CK1 GSK3β β-catenin
APC AXIN destruction complex
β-catenin accumulation
β-catenin β-catenin
β-catenin β-catenin β-catenin
β-catenin
β-catenin
β-catenin
β-catenin
β-catenin
Relocation to nucleus
NUCLEUS
β-catenin
TCF/LEF
Figure 5
Overview of the canonical WNT–β-catenin pathway. The pathway is activated by binding of secreted
WNT ligand to the transmembrane receptor Frizzled and the coreceptors LRP5 or LRP6, resulting in the
activation of DVL. Once activated, DVL inhibits the activity of the APC–AXIN–CK1–GSK3β destruction
complex, thus preventing the phosphorylation and ubiquitin-mediated degradation of β-catenin.
Consequently, stabilized β-catenin accumulates in the cytoplasm and is relocated to the nucleus, where it
acts as a transcriptional coactivator for TCF–LEF-induced gene transcription. Abbreviations: APC,
adenomatous polyposis coli; AXIN, axin; CK1, casein kinase 1; DVL, dishevelled segment polarity protein;
GSK3β, glycogen synthase kinase 3 β; LEF, lymphoid enhancer factor; LRP5/6, low-density lipoprotein
receptor–related protein 5/6; TCF, T-cell factor.

the phosphorylation and subsequent ubiquitin-mediated proteasomal degradation of β-catenin.

CTNNB1 mutations occur in 19–37% of endometrioid carcinomas overall and are more common
in microsatellite stable (MSS) endometrioid tumors (24–52%) than in MSI tumors (11–20%) (6,
61–64). There is almost complete mutual exclusivity between CTNNB1 mutations and KRAS mu-
tations in MSS endometrioid carcinomas, leading to the hypothesis that there is crosstalk between
the WNT–β-catenin and RAS–MAPK pathways, or alternatively, that dysregulation of these
pathways converges on a shared biological process (50). Recent studies have identified signifi-
cant associations between CTNNB1 mutations and poor outcome among low-risk endometrioid
carcinoma patients, suggesting that CTNNB1 mutation has prognostic significance (64–67).
Another molecular mechanism by which the WNT–β-catenin pathway may be perturbed is
via somatic mutation of RNF43, a negative regulator of the pathway that targets the Frizzled
receptor for ubiquitin-mediated degradation. RNF43 is somatically mutated in 18–27% of en-
dometrioid carcinomas (62, 68). However, in contrast to CTNNB1 mutations, RNF43 mutations
are more common in MSI endometrioid carcinomas (50% mutated) than in MSS or MSI-low en-
dometrioid carcinomas (5–14% mutated) (62, 68). Approximately two-thirds of RNF43 mutations
in endometrial cancer are frameshift mutations predicted to cause loss of function, consistent with
the idea that RNF43 is a tumor suppressor (69).
The SOX17 transcription factor also antagonizes WNT signaling by negatively regulating β-
catenin- and TCF–LEF-induced gene transcription. The mutual exclusivity of SOX17 missense
mutations and CTNNB1 mutations in endometrial cancer suggests that SOX17 mutations activate
WNT signaling in this cellular context (6). Overall, SOX17 is somatically mutated in 11.5% of
endometrioid carcinomas, with mutations falling into two major classes: frameshift mutations that
result in loss of SOX17 transcriptional activity and missense mutations that retain transcriptional
activity (70). As shown using immunohistochemistry, low or absent expression of SOX17 in en-
dometrioid carcinomas is associated with advanced tumor stage, high tumor grade (grade 2/3),
and reduced recurrence-free survival (70, 71).
3.1.4. Defects in mismatch repair and replicative repair. MSI, which reflects MMR defects, is
present in approximately 30% of endometrioid carcinomas and is associated with a hypermutated
phenotype (72). In sporadic endometrioid carcinomas, MSI is a consequence of epigenetic silencing
of the MLH1 gene by promoter hypermethylation, which results in defective MMR and the
accumulation of somatic mutations at nucleotide repeats throughout the genome. Some of these
so-called strand slippage mutations may occur by chance in cancer genes and be pathogenic
driver events. Recent studies have pointed to ATR, CTCF, JAK1, RNF43, and RPL22 as driver
genes that frequently sustain pathogenic frameshift mutations at mononucleotide repeats in MSI-
positive endometrioid carcinomas (68, 73–76). ATR is a critical component of the DNA damage
response, CTCF is a zinc finger protein that regulates genome organization and gene transcription,
JAK1 is an oncogenic tyrosine kinase that activates STAT signaling, RNF43 negatively regulates
WNT–β-catenin signaling, and RPL22 is a ribosomal protein.
There have been conflicting reports regarding associations between tumor MSI status and clin-
ical outcome of endometrial cancer patients, possibly reflecting interstudy differences in cohort
size, histotype inclusion, and methodologies used to assess MSI. However, a recent comprehensive
study, which assessed MSI, MMR protein expression by immunohistochemistry and MLH1
promoter methylation in more than 1,000 endometrioid carcinomas demonstrated statistically
significant associations between MMR status and adverse clinicopathologic variables (77). Specif-
ically, epigenetic MMR defects and probable MMR mutations were associated with higher tumor
grade and presence of lymphovascular space invasion; epigenetic MMR defects were also asso-
ciated with later-stage (III/IV) disease (77). In univariate analysis, epigenetic MMR defects were

associated with worse PFS (hazard ratio, 1.37; p ≤ .05; 95% CI, 1.00 to 1.86) (77). However,
multivariate analyses identified no significant associations between MMR status and clinical
outcome (77).
An additional mechanism of genomic instability in endometrioid carcinomas is attributed to
somatic mutation of the exonuclease (proofreading) domain (EDM) of POLE, which encodes the
catalytic subunit of the replicative DNA polymerase epsilon holoenzyme, resulting in an ultramu-
tated tumor phenotype (6). POLE-EDM mutations occur in approximately 5% of endometrioid
carcinomas overall (range 2.7–10.1%) and are more frequent in high-grade endometrioid carci-
noma (mean 12%; range 6.6–15.4%) than in low- or intermediate-grade endometrioid carcinoma
(mean 5.6%; range 3.4–8.8%) (78–82). Importantly, POLE-EDM-mutated endometrioid carci-
noma is associated with a favorable prognosis (6, 78, 80, 83–85), which may reflect more aggressive
treatment of high-grade tumors, increased sensitivity of POLE-mutated tumors to chemotherapy,
and/or enhanced immunogenicity (86–91).

Both MSI-positive endometrial cancers and POLE-mutated endometrial cancers have high
neoantigen loads and immunogenic phenotypes (89, 90). Clinical studies of immune checkpoint
blockade inhibitors in endometrial cancer are ongoing, and findings thus far are encouraging,
particularly for MSI-positive cases. A small Phase II trial of pembrolizumab (Merck), a humanized
monoclonal antibody directed against the programmed death-1 (PD-1) receptor, for the treatment
of MMR-deficient cancers included two endometrial cancer patients; both patients had objective
responses to pembrolizumab as defined by RECIST criteria (92). A subsequent Phase II study
(NCT01876511) of pembrolizumab in patients with previously treated progressive disease and
MMR-deficient cancer included 15 patients with MMR-deficient endometrial cancer (93). In an
interim analysis of this study, patients with MMR-deficient endometrial cancer achieved an ob-
jective response rate of 53% and a disease control rate of 73% (20% complete response, 33%
partial response, 20% stable disease) (93). The KEYNOTE-028 study, a Phase Ib study of pem-
brolizumab for the treatment of PD ligand 1 (PD-L1)-positive advanced solid tumors included 24
endometrial cancer patients; pembrolizumab elicited durable responses and antitumor activity in
this endometrial cancer cohort, with a response rate of 13% and stable disease rate of 13% (94). In
2017, “the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab
(KEYTRUDA, Merck & Co.) for adult and pediatric patients with unresectable or metastatic, mi-
crosatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have
progressed following prior treatment and who have no satisfactory alternative treatment options or
with MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropy-
rimidine, oxaliplatin, and irinotecan” (95). Clinical responses to nivolumab (Bristol-Myers Squibb),
another humanized monoclonal antibody targeting PD-1, have been noted in two endometrial
cancer patients (serous, mixed histologies) with recurrent disease refractory to chemotherapy or
chemo- and radiotherapy (96); one patient had a POLE-mutated and MSI-positive tumor, and the
other patient had an MSH6-mutated and MSI-positive tumor, as determined at the time of conven-
tional therapy (96). A Phase I study of pembrolizumab in patients with PD-L1 expression–positive
cancer included a patient with advanced-stage endometrioid carcinoma who achieved a partial re-
sponse by 8 weeks; the primary and metastatic lesions from this patient both harbored two somatic
mutations in POLE (V411L and R114∗ ), leading to speculation that POLE mutations might iden-
tify a subset of patients who may be particularly responsive to immune checkpoint therapy (97).
3.2. Serous Endometrial Carcinomas

Serous carcinomas are relatively mutationally quiet compared with most endometrioid carcino-
mas but have higher rates of copy number alteration (6). The mutational spectra of serous and

endometrioid carcinomas exhibit some clear distinctions. Mutations in the TP53 tumor suppressor
gene and/or stabilization of the p53 protein are the most frequent molecular aberrations in serous
carcinomas, occurring at frequencies in excess of 85% (Figure 2) (6, 8, 14, 98). Dysregulation
of TP53 or p53 is an early event in the pathogenesis of serous tumors, occurring in a subset of
SEICs, which may precede serous carcinomas (14, 15). The importance of p53 perturbation in
the initiation of serous carcinoma is underscored by a conditional mouse model in which deletion
of Trp53 in the endometrium resulted in the development of type II endometrial carcinomas,
including serous carcinomas (99). In addition to TP53 mutation and/or p53 stabilization, other
molecular events implicated in the pathogenesis of serous carcinoma include somatic mutations
in PPP2R1A, FBXW7, SPOP, CHD4, and TAF1; amplification and/or overexpression of ERBB2,
MYC, and CCNE1 (cyclin-E); and overexpression of p16 and synuclein-γ (15, 98, 100, 101). The
druggable PI3K pathway is also altered at an appreciable frequency in serous carcinomas, prin-
cipally by mutations in PIK3CA (in 17–43% of tumors), with lower frequencies of mutation in
PTEN and PIK3R1 (6, 29, 32, 102–104).
PPP2R1A encodes the PR65A scaffolding subunit of the protein phosphatase 2A holoenzyme,
which is believed to be a tumor suppressor (105, 106). Mutations in PPP2R1A are present in 17–
43% of serous carcinomas and occur early (6, 103, 107). Codons 179, 182, 183, 256, and 257 of
PPP2R1A are major mutational hotspots (107). Functional studies of PPP2R1A mutants are still
at an early stage. However, some hotspot mutants act in a dominant-negative manner to promote
anchorage-independent cell growth in vitro and tumor formation in nude mice, and are associated
with hyperphosphorylation of p70S6K, S6, AKT, and GSK3β (108).
The FBXW7 tumor suppressor gene is somatically mutated in 17–32% of serous carcinomas,
and copy number loss involving FBXW7 occurs in 17–52% of cases (6, 103, 104, 109). In complex
with SKP1 and CUL1, FBXW7 forms an E3 ubiquitin ligase complex (SCFFBXW7 ) that mediates
the ubiquitination and subsequent proteasomal degradation of numerous substrate proteins, some
of which are oncogenic at high levels. A majority of FBXW7 mutations in endometrial cancer
are missense mutations that localize within the C-terminal WD repeats that mediate substrate
binding. Based on functional studies in other cell types, hotspot mutants at Arg465, Arg479, and
Arg505 in the WD repeats can act as dominant-negative mutants that reduce or abolish binding
of mutant FBXW7 to one or more substrate proteins, leading to the inappropriate accumulation
of these proteins. The specific effects of FBXW7 aberrations in endometrial cancer remain to
be determined. However, it has been speculated that FBXW7 mutations in serous carcinoma
may lead to dysregulation of cyclin E, based on the mutual exclusivity of FBXW7 mutations
and CCNE1 (cyclin E) amplification in some tumors (103). Because several SCFFBXW7 substrate
proteins and/or their downstream effectors are druggable or potentially druggable, elucidating
the precise functional consequences of FBXW7 mutations in endometrial carcinoma may have
important therapeutic implications.
SPOP functions in an analogous manner to FBXW7 in that it is the substrate binding com-
ponent of the SPOP–CUL3–RBX1 E3 ubiquitin ligase complex, which mediates ubiquitination
and proteasomal degradation of numerous protein substrates. SPOP has been implicated as a pu-
tative driver gene in serous carcinomas, in which it is somatically mutated in 7–8% of cases (6,
109). The vast majority of SPOP mutations in serous carcinomas are missense mutations in the
MATH domain, which binds proteins targeted for degradation (6, 104, 109). The functional ef-
fects of endometrial cancer–specific SPOP mutations are not well defined, but some mutations
have been reported to result in increased levels of the TRIM2, AGR2, and SRC3/NCOA3/AIB1
oncoproteins and enhanced degradation of the DEK, BRD2, BRD3, and BRD4 proteins (110).
CHD4, a catalytic subunit of the nucleosome remodeling and deacetylase (NuRD) complex,
which remodels chromatin, is somatically mutated in 10–19% of serous carcinomas (6, 104, 109).

Most CHD4 mutations in serous tumors are missense mutations, many of which localize to the
central ATPase or helicase domain that catalyzes ATP-dependent nucleosome repositioning by
the NuRD complex. Among other activities, CHD4 participates in the early stages of the cellular
response to DNA damage induced by double-strand breaks and has been classified as a caretaker
of genomic integrity (111–113). Although siRNA depletion of CHD4 in a breast cancer cell line
confers increased sensitivity to PARP inhibition (114), the functional effects and clinical relevance
of somatic missense mutations in CHD4 have yet to be determined.
TAF1 is a critical subunit of the TFIID basal transcription factor complex, which binds to core
promoters and facilitates assembly of the RNA–polymerase II preinitiation complex. The TFIID
complex is comprised of the TATA-binding protein and 13 TAF proteins, including TAF1.
Recent exome sequencing of serous carcinomas led to the nomination of TAF1 as a candidate
driver gene (104). Mutations in this gene have been described in 5–13% of cases (104), with a
subset of mutations occurring at highly evolutionarily conserved residues, including residues in

the putative histone acetyltransferase domain (104).
Dysregulation of the ERBB2/HER2 receptor tyrosine kinase resulting from gene amplification
and/or protein overexpression has been implicated in serous carcinoma at variable frequency
(17–57%) (115). Clinical studies assessing the efficacy of ERBB2/HER2 inhibitors in endometrial
cancer are underway. An early retrospective review of a tumor registry identified two patients with
HER2-positive serous carcinoma who exhibited clinical responses to trastuzumab (Genentech),
a humanized monoclonal antibody directed against HER2 (116, 117). However, a Phase II trial
of trastuzumab in women with advanced or recurrent HER2-positive endometrial cancer found
no evidence for single-agent activity (118), although it has been suggested that this study may
have been underpowered to detect an effect (119). A Phase II trial of lapatinib (Novartis), a
small-molecule inhibitor of ERBB2/HER2 and EGFR, in patients with recurrent or persistent
endometrial cancer reported limited clinical activity as a single agent in molecularly unselected
patients (120).
3.3. Clear Cell Endometrial Carcinomas

Clear cell carcinoma accounts for fewer than 5% of all endometrial carcinomas at initial pre-
sentation. Immunoreactivity for Napsin A, an aspartic protease, is significantly more frequent
among clear cell carcinomas (67–93%) than among serous (8–22%) or endometrioid carcinomas
(0–10%) (reviewed in Reference 121). Similarly, immunoreactivity for HNF1B, a homeodomain-
containing transcription factor, is also more commonly observed among clear cell (83–94%) than
serous (23–26%) or endometrioid (9–39%) carcinomas (122–124).
Clear cell carcinomas were not analyzed by TCGA; therefore, the molecular features of this
subtype remain relatively underexplored in comparison with endometrioid or serous carcinomas.
Although a small number of clear cell carcinoma exomes have been sequenced (125), most muta-
tional studies of this subtype have utilized targeted sequencing with a focus on genes implicated in
other histotypes of endometrial cancer or on clinically actionable genes. In all mutational studies
of clear cell carcinoma reported to date, TP53 is the most frequently mutated gene, undergo-
ing somatic mutations in 31–50% of cases (18, 125–128) and exhibiting aberrant protein (p53)
expression in 34% of cases (Figure 3) (18). Other cancer genes mutated in clear cell carcinoma
are PPP2R1A (16–32%), PIK3CA (14–37%), FBXW7 (7–27%), PTEN (0–25%), KRAS (0–13%),
ARID1A (14–22%), SPOP (14–29%), and POLE (0–6%) (18, 102, 125–128). In addition, relatively
frequent genomic gains have been reported for CCNE1 (18%), ERBB2 (11%), and CEBP1 (11%),
and genomic deletions have been observed for DAXX (11%) (18). MSI or abnormal MMR pro-
tein expression have been detected in 0–19% of cases (18, 125–128). Loss of BAF250A (ARID1A)
expression has been observed in 26% of cases (26).
A recurring theme that has emerged from molecular studies of clear cell carcinoma is that
it shares molecular features with both serous and endometrioid carcinomas, an observation that
was made in the very first molecular analysis of clear cell tumors (126). Given that there is only
moderate interobserver agreement in the histopathologic diagnosis of clear cell carcinoma (129,
130), some of the molecular similarities of this subtype to serous and endometrioid carcinomas
might be attributed to tumor misclassification. However, an analysis of a small series of consensus
clear cell carcinomas, agreed upon by at least three of five gynecologic pathologists, reported
mutations in PIK3CA exons 9 and 20 (11%), KRAS (22%), and PIK3R1 (11%), and estrogen
receptor positivity (8%) (129). A more extensive interrogation of the genomic features of a much
larger series of clear cell carcinomas will be required to formally define the genomic landscape
of this subtype and to determine whether there are molecular alterations that are unique to, or
significantly enriched in, clear cell tumors compared to other subtypes.
3.4. Uterine Carcinosarcomas

The molecular pathogenesis of uterine carcinosarcoma has received increasing attention in the
past decade, and this subtype has undergone an integrated genomic analysis by TCGA (131).
Most uterine carcinosarcomas are aneuploid, and approximately 90% have undergone at least one
whole genome doubling event (131). In TCGA, the expression of 131 epithelial-to-mesenchymal-
related genes was more variable among uterine carcinosarcomas than among other tumor types
(131). Somatic mutational analyses have consistently demonstrated that TP53 is the most com-
monly mutated gene in uterine carcinosarcoma, with mutation rates ranging from 64% to 91%
(24, 25, 29, 131–133). Other frequently mutated genes are FBXW7 (11–38%), PTEN (18–47%),
PIK3CA (15–41%), CHD4 (16–17%), ARID1A (10–24%), KRAS (9–29%), PPP2R1A (13–27%),
and FOXA2 (5–15%) (24, 25, 29, 102, 131–134). Based on comparisons of the mutational reper-
toire of uterine carcinosarcoma with those of serous and endometrioid carcinomas, 67–78% of
uterine carcinosarcomas molecularly resemble serous carcinomas, and 22–33% molecularly re-
semble endometrioid carcinomas (24, 131).
Other genes that are putative drivers of uterine carcinosarcoma are RB1 (4–11%), U2AF1
(4%), ZBTB7B (11%), ARHGAP35 (11%), SPOP (7–18%), HIST1H2BJ (7%), and HIST1H2BG
(7%) (25, 131). Interestingly, RB1, U2AF1, and ZBTB7B have been nominated as putative driver
genes in carcinosarcomas but not in serous or endometrioid carcinomas (131). Similarly, a broad
region of copy number gain on chromosome 5p, which includes the TERT cancer gene, occurs at
higher frequency in uterine carcinosarcoma than in carcinomas (50% versus 17%, respectively)
(25). Additional cancer genes within regions of recurring focal amplification or deletion in uterine
carcinosarcomas include the oncogenes TERC, FGFR3, MYC, KAT6A, MDM2, ERBB2, CCNE1,
and BCL2L1 (within amplifications) and the tumor suppressor genes PTPRD and RB1 (within
deletions) (131).
Regarding potentially clinically relevant events, POLE mutations, which are a favorable prog-
nosticator in endometrioid carcinoma, occur in 2–4% of uterine carcinosarcomas (24, 131, 133).
MSI, a biomarker of sensitivity to immune checkpoint therapy, has been reported in uterine car-
cinosarcomas at frequencies of 3.5%, 6%, and 21% (References 131, 133, and 23, respectively),
and immunohistochemical loss of MMR protein expression has been noted in 3–6% of cases
(24, 135). Of note, a case report has described a durable response to pembrolizumab in a pa-
tient with a POLE-mutated, MSS uterine carcinosarcoma (136). In contrast to POLE mutations
and MMR defects, which are relatively uncommon in UCS, aberrations of the druggable PI3K
pathway are relatively common, occurring in 62–67% of tumors (24, 131). Other less frequently
altered gene sets highlighted by TCGA as potentially clinically relevant in carcinosarcomas include

those that may be associated with sensitivity to CDK inhibitors (CCNE1, CDKN2B, CDKN2A,
CCND1; altered in 12.5% of uterine carcinosarcomas), mTOR inhibitors (FBXW7, AKT2, STK11;
39%); anti-HER2 therapy (ERBB2, ERBB3; 11%), PARP inhibitors (ATM, BRCA2; 9%), dasatinib
(Bristol-Myers Squibb) (EPHA5, DDR2; 7%), FGFR inhibitors (FGFR1, FGFR2; 3.5%), HDAC
inhibitors (BRD3, SMARCA4; 3.5%), imatinib (Novartis) (PDGFRB; 7%), ALK inhibitors (ALK;
5%), Notch inhibitors (NOTCH1; 3.5%), and hedgehog inhibitors (PTCH1; 2%) (131).
4. MOLECULAR SUBGROUPS OF ENDOMETRIOID AND SEROUS

ENDOMETRIAL CARCINOMA: CLASSIFICATION AND
PROGNOSTIC IMPLICATIONS
The integrated genomic analysis of endometrioid and serous carcinomas by TCGA resulted in
the description of four distinct molecular subgroups: POLE (ultramutated), MSI (hypermutated),
copy number low (endometrioid), and copy number high (serous-like) (Figure 6), based on a
consideration of somatic mutation rates, MSI status, and somatic copy number status (6). The
POLE (ultramutated) subgroup had an exceedingly high mutation rate (232 × 10−6 mutation/Mb)
in conjunction with somatic mutations in the exonuclease domain of POLE and a higher pro-
portion of C > T transversions than the other molecular subgroups. The MSI (hypermutated)
subgroup was characterized by a high mutation rate (18 × 10−6 mutations/Mb) accompanied by
MSI and frequent hypermethylation of the MLH1 promoter, indicating defective MMR. The
copy-number-low (endometrioid) subgroup was copy number quiet, with a relatively low over-
all mutation rate (2.9 × 10−6 mutations/Mb). The copy-number-high (serous-like) subgroup was
characterized by high-level copy number alterations, frequent (92%) somatic mutations in TP53,
and a relatively low mutation rate (2.3 × 10−6 mutations/Mb). The number of candidate driver
(pathogenic) genes ranged from 190 genes in the POLE subgroup, to 21 genes in the MSI subgroup,
to 16 genes in the copy-number-low subgroup, to 8 genes in the copy-number-high subgroup (6).
With the exception of a single tumor, all serous carcinomas in the TCGA study were within the
copy-number-high subgroup. In contrast, endometrioid carcinomas were distributed among all
four subgroups as follows: POLE subgroup, 6.4% of grade 1/2 and 17.4% of grade 3 endometrioid
carcinomas; MSI subgroup, 28.6% of grade 1/2 and 54.3% of grade 3 endometrioid carcinomas;
copy-number-low subgroup, 60.0% of grade 1/2 and 8.7% of grade 3 endometrioid carcinomas;
copy-number-high subgroup, 5.0% of grade 1/2 and 19.6% of grade 3 endometrioid carcinomas.
Mixed-histology tumors were distributed among the copy-number-high and copy-number-low
subgroups (6).
In terms of clinical outcome, the POLE subgroup had the most favorable prognosis, and the
copy-number-high subgroup had the poorest prognosis within the TCGA cohort (6). Because inte-
grated genomic analysis is not currently practical in the clinical setting, there has been considerable
interest in developing a panel of tests that recapitulate the TCGA classification in order to evaluate
the utility of such classifiers in risk prediction. One classification scheme, referred to as ProMisE
(Proactive Molecular Risk Classifier for Endometrial Cancer), consists of sequential testing and de-
cision making, beginning with immunohistochemistry for MLH1/MSH2/MSH6/PMS2 to detect
MMR repair abnormalities, followed by sequencing to identify POLE-EDM mutations, followed
by immunohistochemistry for p53 to identify p53-abnormal and p53-wild-type tumors (137). In
terms of histotype reproducibility, consensus interobserver agreement rates among seven pathol-
ogists vary for each ProMisE subgroup, with 65% agreement for the POLE-EDM-mutated sub-
group, 58% for the MMR-deficient subgroup, 90% for the p53-wild-type subgroup, and 39%
for the p53-abnormal subgroup (138). The four subgroups defined by the ProMisE classifica-
tion scheme recapitulate the differences in clinical outcome observed in the TCGA subgroup

PM14CH14_Bell
ARI
POLE
8 December 2018
(ultramutated) MSI (hypermutated) Copy number low (endometrioid) Copy number high (serous-like)
500
50
5
per Mb
14:11
Mutations
0.5 n = 17 n = 65 n = 90 n = 60
100
80
60
40
20
Substitution
frequency (%)
0
POLE
MSI/MLH1
CN cluster
PTEN
TP53
Histology
Tumor grade
Nucleotide substitutions POLE mutations MSI DNA methylation CN cluster Mutations Histology Tumor grade
CA CG CT TA V411L P286R Other MSI high MSI low MLH1 silent 1 2 3 4 Nonsense Missense Serous Mixed 3 2 1
TC TG MS stable NA Frameshift Endometrioid
Figure 6
TCGA molecular subgroup classification of endometrioid and serous endometrial carcinomas (6). Endometrioid and serous endometrial carcinomas were classified into
four molecular subgroups by TCGA based on nucleotide substitution frequencies and patterns, MSI status, and copy number status. Mutation frequencies (shown on the
vertical axis, top panel) are plotted for each tumor (horizontal axis). Nucleotide substitutions are shown in the middle panel, with a high frequency of C to A transversions
in the samples with POLE exonuclease mutations. Abbreviations: CN, copy number; MS, microsatellite; MSI, microsatellite instability; TCGA, The Cancer Genome
www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma

Atlas. Figure adapted from Reference 6 with permission from RightsLink Permissions Springer Customer Service Centre GmbH.
357
classification (137). Additionally, a comparison of the ProMisE classifier with the 2013 Euro-
pean Society for Medical Oncology risk stratification system showed refinements in risk as-
sessment by ProMisE (139). ProMisE was developed in accordance with Institute of Medicine
guidelines, and the utility of the ProMisE classifier is ready for assessment in clinical trials
(140).
Similar to ProMisE, Stelloo and colleagues have described a panel of molecular tests that
classify endometrial tumors into four subgroups, POLE mutated, MSI positive, p53 mutant, and
no specific molecular profile (NSMP); the POLE-mutated and MSI-positive subgroups exhibited
the most favorable outcomes (67, 128). A follow-up study of a large (n = 834) cohort of early-
stage endometrioid endometrial tumors, collected as part of the PORTEC-1 and PORTEC-2
clinical trials, reported that consideration of POLE, MSI, p53, CTNNB1, and L1CAM status
together with the extent of lymphovascular space invasion improved the prediction for risk of
disease recurrence compared with risk stratification based solely on clinicopathological features
(67). It has recently been noted that the presence of 1q32.1 amplification within the NSMP group
is an adverse prognosticator and that inclusion of this variable strengthens the ability of this testing
strategy to predict risk of disease recurrence (141).
5. GERMLINE GENETIC PREDISPOSITION TO

ENDOMETRIAL CANCER
Up to 5% of endometrial cancers are familial, arising as a result of inherited genetic suscepti-
bility. The majority of inherited endometrial cancers occur in the context of Lynch syndrome,
a highly penetrant, autosomal dominant familial cancer syndrome caused by the inheritance of
a germline loss-of-function mutation in an MMR gene (MLH1, MSH2, MSH6, or PMS2) or a
germline deletion encompassing the 3 region of EpCAM that leads to transcriptional read-through
and epigenetic silencing of the adjacent MSH2 gene. The associated lifetime risk of developing
endometrial cancer is 25–60% (mean age at diagnosis is 48–62 years) (142). The histology of
Lynch syndrome–associated endometrial cancer varies by study but is generally predominated by
endometrioid carcinomas (56–96% of cases), with serous, clear cell, mixed, mucinous, undifferen-
tiated carcinomas and carcinosarcomas accounting for the remaining cases (143–147). It has been
suggested that clinical trials of immune checkpoint inhibitors should evaluate Lynch syndrome–
related endometrial cancer and sporadic MSI-positive endometrial cancer separately, based on
differences in the immune cell content of tumors from these two patient groups (148).
In addition to being at increased risk for endometrial cancer, Lynch syndrome patients are also
at increased risk for colorectal, ovarian, gastric, small bowel, breast, and prostate cancers, as well
as cancers of the hepatobillary tract, urinary tract, brain, and pancreas, and sebaceous neoplasms.
Endometrial cancer is a so-called sentinel cancer in Lynch syndrome, often occurring before the
onset of colorectal cancer. As such, universal tumor testing of endometrial cancers for MSI and/or
loss of MMR protein expression, followed by MLH1 promoter methylation analysis, can be used to
identify potential Lynch syndrome patients, for subsequent confirmatory germline genetic testing
(Figure 1) (149). However, inconclusive tumor test results and less than 100% genetic counseling
uptake rates represent challenges in clinical practice (149, 150).
In addition to Lynch syndrome, increased genetic predisposition to endometrial cancer
also occurs in the context of POLD1-associated polymerase proofreading-associated polyposis
(151). Increased risk of endometrial cancer also occurs in PTEN-associated Cowden syndrome;
the lifetime risk of endometrial cancer in PTEN mutation carriers ranges from 19% to 28%
(152).

6. SUMMARY
Endometrial carcinomas can be classified according to pathogenetic, histopathologic, and molec-
ular features. There is substantial, but incomplete, overlap between these three descriptors. En-
dometrioid and serous carcinomas, which represent prototypical type I and type II endometrial
tumors according to Bokhman’s pathogenetic descriptors, were classified by TCGA into four dis-
crete molecular subgroups, referred to as POLE (ultramutated), MSI (hypermutated), copy num-
ber low (endometrioid), and copy number high (serous-like); endometrioid tumors are distributed
among each of the four molecular subgroups, whereas the vast majority of serous tumors are in
the copy-number-high subgroup. A large body of work now supports the initial TCGA finding
that the category of POLE-ultramutated endometrioid carcinomas, which includes some high-
grade endometrioid carcinomas, is associated with favorable clinical outcomes. Surrogate tests for
TCGA’s molecular classification are being evaluated for their potential utility in risk stratification.
Clear cell carcinoma, which is sometimes difficult to reproducibly classify by histopathology, has
some overlapping molecular feature with serous and endometrioid carcinomas, but it has not been
subjected to an integrated genomic analysis, and much remains to be done to fully understand its
molecular etiology. Although uterine carcinosarcoma shares some molecular features with serous
and endometrioid carcinomas, it also has distinguishing features, including more variable expres-
sion of epithelial-to-mesenchymal-related genes. The application of recently developed genomic
technologies and bioinformatics approaches to study endometrial tumors has provided unprece-
dented insight into the molecular etiology of this disease. The challenge now is to determine
whether specific molecular features can be leveraged for patient prognosis and treatment.
DISCLOSURE STATEMENT
D.W.B. is an inventor on US patent no. 7,294,468, titled Method to Determine Responsiveness
of Cancer to Epidermal Growth Factor Receptor Targeting Treatments, which has been licensed
and provides royalty income.
ACKNOWLEDGMENTS
We apologize to those authors whose work we could not cite due to space limitations. This work
was supported by the Intramural Research Program of the National Human Genome Research
Institute at the National Institutes of Health (projects ZO1 HG200338 and ZO1 HG200379 to
D.W.B.).
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PM14_TOC ARI 21 December 2018 8:18
Annual Review
of Pathology:
Mechanisms of
Disease
Contents Volume 14, 2019
Polyglutamine Repeats in Neurodegenerative Diseases

Andrew P. Lieberman, Vikram G. Shakkottai, and Roger L. Albin p p p p p p p p p p p p p p p p p p p p p p p p 1
Epstein–Barr Virus and Cancer

Paul J. Farrell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p29

Exposure to Ultraviolet Radiation in the Modulation
of Human Diseases
Prue H. Hart, Mary Norval, Scott N. Byrne, and Lesley E. Rhodes p p p p p p p p p p p p p p p p p p p p p p p55
Insights into Pathogenic Interactions Among Environment, Host,
and Tumor at the Crossroads of Molecular Pathology and
Epidemiology
Shuji Ogino, Jonathan A. Nowak, Tsuyoshi Hamada, Danny A. Milner Jr.,
and Reiko Nishihara p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p83
Pathological Issues in Dystrophinopathy in the Age
of Genetic Therapies
Nazima Shahnoor, Emily M. Siebers, Kristy J. Brown, and Michael W. Lawlor p p p p p p p 105
Pathogenesis of Rickettsial Diseases: Pathogenic and Immune
Mechanisms of an Endotheliotropic Infection
Abha Sahni, Rong Fang, Sanjeev K. Sahni, and David H. Walker p p p p p p p p p p p p p p p p p p p p p 127
Innate Immune Signaling in Nonalcoholic Fatty Liver Disease
and Cardiovascular Diseases
Jingjing Cai, Meng Xu, Xiaojing Zhang, and Hongliang Li p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 153
Immunological Basis for Recurrent Fetal Loss
and Pregnancy Complications
Hitesh Deshmukh and Sing Sing Way p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185
Opportunities for microRNAs in the Crowded Field
of Cardiovascular Biomarkers
Perry V. Halushka, Andrew J. Goodwin, and Marc K. Halushka p p p p p p p p p p p p p p p p p p p p p p p 211
Molecular Pathogenesis of the Tauopathies
Jürgen Götz, Glenda Halliday, and Rebecca M. Nisbet p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 239
PM14_TOC ARI 21 December 2018 8:18
Pathophysiology of Sickle Cell Disease

Prithu Sundd, Mark T. Gladwin, and Enrico M. Novelli p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 263
Malformations of Cerebral Cortex Development: Molecules
and Mechanisms
Gordana Juric-Sekhar and Robert F. Hevner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293
Clinical Metagenomic Next-Generation Sequencing
for Pathogen Detection
Wei Gu, Steve Miller, and Charles Y. Chiu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 319
Molecular Genetics of Endometrial Carcinoma
Daphne W. Bell and Lora Hedrick Ellenson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 339
Type I Interferons in Autoimmune Disease

Mary K. Crow, Mikhail Olferiev, and Kyriakos A. Kirou p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
Systems-Wide Approaches in Induced Pluripotent Stem Cell Models

Edward Lau, David T. Paik, and Joseph C. Wu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 395
Pathology and Pathogenesis of Chagas Heart Disease
Kevin M. Bonney, Daniel J. Luthringer, Stacey A. Kim, Nisha J. Garg,
and David M. Engman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 421
Modeling Disease with Human Inducible Pluripotent Stem Cells
Rodrigo Grandy, Rute A. Tomaz, and Ludovic Vallier p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 449
RNA Binding Proteins and the Pathogenesis of Frontotemporal
Lobar Degeneration
Jeffrey W. Hofmann, William W. Seeley, and Eric J. Huang p p p p p p p p p p p p p p p p p p p p p p p p p p p 469
Cellular and Molecular Mechanisms of Prion Disease
Christina J. Sigurdson, Jason C. Bartz, and Markus Glatzel p p p p p p p p p p p p p p p p p p p p p p p p p p p p 497
Errata
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PM14CH14_Bell ARI 8 December 2018 14:11

Annual Review of Pathology: Mechanisms of Disease

Annu. Rev. Pathol. Mech. Dis. 2019. 14:339–67 Keywords

2. HISTOPATHOLOGY OF ENDOMETRIAL CARCINOMA

340 Bell · Ellenson

WORLD HEALTH ORGANIZATION 2014 CLASSIFICATION OF ENDOMETRIAL

Endometrioid carcinoma, usual type

supportive diagnostic criteria, as is discussed in this section. In addition, recent next-generation

2.1. Endometrioid Carcinoma

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 341

342 Bell · Ellenson

2.2. Serous Carcinoma

2.3. Clear Cell Carcinoma

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 343

344 Bell · Ellenson

2.4. Undifferentiated and Dedifferentiated Carcinoma

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 345

3. MOLECULAR PATHOGENESIS OF ENDOMETRIAL CARCINOMAS

3.1. Endometrioid Endometrial Carcinomas

3.1.1. The PI3K–PTEN–AKT–mTOR pathway. Signal transduction via the PI3K–PTEN–

346 Bell · Ellenson

PTEN LKB1 CYTOPLASM

Cell Cell survival, cell Translation,

endometrioid carcinoma, since it is present in a relatively large proportion of endometrial hyper-

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 347

348 Bell · Ellenson

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 349

3.1.3. The canonical WNT–β-catenin pathway. The canonical WNT–β-catenin pathway

350 Bell · Ellenson

the phosphorylation and subsequent ubiquitin-mediated proteasomal degradation of β-catenin.

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 351

and/or enhanced immunogenicity (86–91).

3.2. Serous Endometrial Carcinomas

352 Bell · Ellenson

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 353

subset of mutations occurring at highly evolutionarily conserved residues, including residues in

3.3. Clear Cell Endometrial Carcinomas

3.4. Uterine Carcinosarcomas

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 355

4. MOLECULAR SUBGROUPS OF ENDOMETRIOID AND SEROUS

356 Bell · Ellenson

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma

strategy to predict risk of disease recurrence (141).

5. GERMLINE GENETIC PREDISPOSITION TO

358 Bell · Ellenson

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 359

360 Bell · Ellenson

and PTEN genes in endometrial carcinoma. Cancer Res. 65:10669–73

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 361

362 Bell · Ellenson

dometrial cancer genomes. Cell 155:858–68

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 363

364 Bell · Ellenson

with diagnostic challenges. Arch. Pathol. Lab. Med. 138:343–50

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 365

366 Bell · Ellenson

www.annualreviews.org • Molecular Genetics of Endometrial Carcinoma 367

Contents Volume 14, 2019

Polyglutamine Repeats in Neurodegenerative Diseases

Epstein–Barr Virus and Cancer

Paul J. Farrell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p29

Pathophysiology of Sickle Cell Disease

Type I Interferons in Autoimmune Disease

Systems-Wide Approaches in Induced Pluripotent Stem Cell Models