ORIGINAL ARTICLE

TP53 Mutations in Endometrial Cancers

Relation to PTEN Gene Defects
Aneta Janiec-Jankowska, PhD,* Bo¼ena Konopka, PhD,* Cyprian Goluda, MD,Þ
and Urszula Najmoaa, MSc*
Downloaded from https://journals.lww.com/ijgc by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3YzRZ0r/T2spjoHoc3GaslZloSNOhvOIH5C3/pQJbv6eJiE+JPS0c3g== on 08/01/2018

Objective: The PTEN and TP53 genes participate in the carcinogenesis of many malig-
nancies, but the role of both genes in endometrial carcinogenesis is not fully elucidated.
The aim of the study was to determine the quality and the frequency of incidence of TP53
and PTEN gene mutations and to assess their coexistence in endometrial cancers. Besides
that, the correlation was studied between the detected defects and clinicohistopathological
characteristics of the studied endometrial cancers.
Methods: The study material included DNA isolated from 81 endometrial cancers. The
incidence of TP53 and PTEN gene mutations was assessed using polymerase chain
reactionYsingle-strand conformation polymorphism and sequencing techniques.
The statistical analysis of the results was performed using W2 test.
Results: In 64.2% of the 81 endometrial cancers, mutations occurred in TP53 and/or PTEN
genes: in 16.1%, mutations occurred only in TP53; in 33.3%, only in PTEN gene; and in
14.8%, in both TP53 and PTEN genes. In 35.8% of cases, no mutations were found in these
genes. No statistically significant relationship was found between the incidence of mutations
in TP53 gene and that in PTEN gene (P = 0.986). The incidence of mutations in PTEN gene
was higher in medium and poorly differentiated endometrial cancers than in well-differentiated
ones and was statistically significant (G2 + G3 vs G1; P = 0.049). Besides that, mutations in
PTEN gene occurred significantly more frequently in patients younger than 55 years than in
older women (Q55 years; P = 0.027). No similar differences were found in TP53 gene.
Conclusions: The results of the study demonstrate that TP53 gene mutations occur in
some of endometrioid endometrial cancers in the presence of PTEN gene mutations, sug-
gesting that both these genes participate in the development of these tumors.
Key Words: Endometrial carcinoma, TP53, PTEN, Mutations

Received May 11, 2009, and in revised form July 10, 2009.
Accepted for publication October 11, 2009.
(Int J Gynecol Cancer 2010;20: 196Y202)

*Endocrinology Department, Maria Sklodowska-Curie Memorial

Cancer Center and Institute of Oncology, Warsaw; and †2nd
Clinic of Gynaecology, Medical Academy, Wroclaw, Poland.
Address correspondence and reprint requests to
Aneta Janiec-Jankowska, PhD, Endocrinology Department,
Maria Sklodowska-Curie Memorial Cancer Center and Institute
of Oncology, 5 W.K. Roentgen, 02-781 Warsaw, Poland.
E-mail: ajankowska@coi.waw.pl.
This study was funded by Maria Sklodowska-Curie Memorial
Cancer Center and Institute of Oncology, Warsaw, Poland
(2003Y2006).
Copyright * 2010 by IGCS and ESGO
ISSN: 1048-891X
DOI: 10.1111/IGC.0b013e3181c83675
T heper incidence of endometrial cancer in Poland is 11.3
100,000 women, which corresponds to the fifth place
among the most frequently developing female malignan-
cies.1 Two basic clinical-histological types are distinguished:
type 1Vendometrioid, including estrogen-dependent can-
cers developing usually from hyperplasia, characterized by
low malignancy and infrequent metastasizing and type 2V
nonendometrioid, including estrogen-independent cancers
such as serous and clear cell cancers, with higher malignancy
and more frequent metastasizing.2 These cancers differ
between themselves both in the disease course and suscep-
tibility to treatment. Molecular studies demonstrated that
both types of endometrial cancer differ in the quality of

196 International Journal of Gynecological Cancer & Volume 20, Number 2, February 2010

Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer & Volume 20, Number 2, February 2010
genetic changes determining their structural and biological
characteristics. Approximately 30% of type 1 endometrial
cancers are characterized by microsatellite DNA instability,
mutations in K-RAS and A-cateninYencoding (CTNNB1)
genes, and numerous mutations in PTEN gene.3,4 Type 2
nonendometrial cancers are characterized by very frequent
(even 90%) development of mutations in TP53 gene and
overexpression of TP53 protein and development of over-
expression of HER-2/neu gene.3,5
The mutations in PTEN gene are best documented
among the genetic lesions identified as yet in sporadic
endometrial cancers. The PTEN gene product, that is,
protein-lipid phosphatase, participates in the regulation of
many important processes in the cell, such as prolifera-
tion, migration, adhesion, and apoptosis, and is also a
suppressor of tumor growth. PTEN mutations are detected
even in almost 80% of endometrial malignancies, mainly
type 1 cancers. They are also present in endometrial hy-
perplasia, which can suggest their role in early carcinogenesis
of that malignancy.6 Our earlier studies7 demonstrated that
PTEN gene mutations in endometrial cancer frequently
coexisted with lesions in other genes such as CTNNB1,
K-RAS, and CMYC and with microsatellite instability, but
in some endometrial cancers, no genetic defects could have
been detected. Among the factors connected with endome-
trial cancer, TP53 gene arouses ever greater interest. The
TP53 tumor suppressor gene is located in chromosome 17,
(locus 17p13.1); it includes a DNA fragment with 20,303
base pairs and encodes TP53 protein (53 kd).8 The
phosphoprotein encoded by TP53 gene participates in cell
cycle regulation, DNA repair systems, and in apoptosis.
Earlier studies failed to confirm PTEN and TP53 cooper-
ation in endometrial carcinogenesis.9 However, recent
studies indicate common activity pathways of both genes
in cancer cells.10 Stambolic et al11 demonstrated that the
promoter of PTEN gene contains a binding site for TP53.
TP53 gene mutations can have an influence on PTEN
activity, which, in turn, can play a role in the development
of a malignant process in cells. A similar mechanism was
demonstrated by Oki et al12 in gastric cancer. Such con-
nections of these 2 genes can be of importance also for
endometrial carcinogenesis processes. Our studies dem-
onstrated that some endometrioid cancers have simulta-
neous mutations in TP53 and PTEN genes, which can have
an influence on cancer phenotype and further growth.
Because the information about that subject is still scarce in
the literature, we suggest to start such studies in endo-
metrial cancer.
Taking these facts into account, we analyzed in the
present study the occurrence of TP53 and PTEN gene
mutations in 81 endometrial cancers. Then, we compared
the incidence and coexistence of mutations in TP53 and
PTEN genes. Besides that, we checked the correlation
between the detected defects and clinical and histopatho-
logical features of the studied endometrial cancers. We
expect that the results of this study would help to better
learn and understand the complex mechanisms of carci-
nogenesis and etiopathogenesis of sporadic endometrial
cancer.
* 2010 IGCS and ESGO
Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
TP53 and PTEN Mutations
MATERIALS AND METHODS
Tumor Samples
Eighty-one endometrial cancers were studied in women
who underwent surgery in the 2nd Clinic of Gynaecology of
Medical Academy, Wroclaw, Poland. The ages of the studied
patients were 33 to 85 years (mean, 61.3 years). The clinical
grade of progression of the studied cancers was assessed
according to the International Federation of Gynecology and
Obstetrics 1988 (FIGO-1988) classification.13 In 65 cases, the
cancers were limited to the uterine corpus (FIGO stage I), and
in 28, they were located within the endometrium (FIGO stage
IA), whereas in 37 cases, myometrium infiltration (FIGO stage
IB and C) was found. In 4 cases, cancer spread to the uterine
cervix (FIGO stage IIA), and in 12 patients, it extended beyond
the uterus to other tissues (FIGO stage III). The histopatho-
logical assessment of endometrial cancers was carried out ac-
cording to the World Health Organization classification.14 In 81
cases, endometrioid endometrial cancers (EC) were diagnosed.
The morphological differentiation of the studied ECs was as
follows: 33 cancers were well differentiated (G1); 32, medium
differentiated (G2); and 16, poorly differentiated (G3).
DNA Isolation
The study material included DNA isolated from en-
dometrial cancers. The material, sampled immediately after
surgical uterectomy, was frozen in liquid nitrogen and stored
at j70-C until tests were performed. The genomic DNA was
isolated by the phenol-chloroform method with proteinase
K and was used for polymerase chain reaction (PCR).
Study of Mutations in TP53 and PTEN
GenesVPCR
In PCR, fragments of the studied TP53 and PTEN
genes including all exons together with adjacent intron sec-
tions were amplified using the earlier described primers.15Y17
Polymerase chain reaction amplification was performed in
25 KL total volume. To 200 ng of genomic DNA, the fol-
lowing mixture was added: 10 PCR buffer (20-mmol/L Tris/
HCl pH 8.4, 50-mmol/L KCl; Perkin Elmer [PE] Applied
Biosystems); 1.5-mmol/L MgCl2; 200-Hmol/L deoxynucleo-
tide triphosphate; 1 U of AmpliTaq Gold polymerase (PE);
and appropriate primers in a 0.5-Hmol/L concentration each.
Polymerase chain reaction amplification reactions were per-
formed in Gene Amp 9600 thermocycler (PE) under the fol-
lowing conditions: denaturation at 95-C for 10 minutes and
35 polimerization cycles (95-C for 30Y60 seconds; 50Y60-C
for 60Y120 seconds, depending on the exon studied; 72-C for
30Y60 seconds; and final extension of 72-C for 10 minutes).
Single-Strand Conformation
Polymorphism Analysis
For the search for mutations in TP53 and PTEN genes,
the single-strand conformation polymorphism technique was
applied as the screening method, as earlier described.7
Sequencing Analysis (ABI PRISM 377)
The samples suspected of mutation presence were se-
quenced. The PCR products were purified in Centricon-100
197
Janiec-Jankowska et al International Journal of Gynecological Cancer & Volume 20, Number 2, February 2010

TABLE 1. TP53 mutations in endometrial cancers

Exon Codon/Nucleotide Mutation Predicted Effect Type Frequency in EC
4 86/258 GCAYGCG Ala86Ala S 1
4 125/375 ACGYACC Thr125Thr S 1
5 150/448 ACAYTCA Thr150Ser MS 1
6 193Y201/577Y604 Del 27 bp Del 9 aac* Del 1
7 227/679 Ins A Stop 228 Ins 1
7 242/724 TGCYAGC Cys242Ser MS 12
7 253/757 ACCYCCC Thr253Pro MS 2
7 257/768 CTGYATG Leu257Met MS 1
8 277/830 TGTYTTT Cys277Phe MS 1
8 280/838 AGAYGGA Arg280Gly MS 1
8 302/904 GGGYTGG Gly302Trp MS 2
10 351/1052 AAGYATG Lys351Met MS 6
Total 30
*Deleted amino acids: His-Leu-Ile-Arg-Val-Glu-Gly-Asn-Leu.
EC, endometrioid (type 1) endometrial carcinoma; Del, deletion; Ins, insertion; MS, missense mutation; S, silent mutation.

(Millipore) columns and then were amplified in PCR reaction
using BigDye Terminator RR Mix (PE) according to the rec-
ommended procedure in DNA thermocycler 9600 (PE) under
the following conditions: denaturation at 95-C for 5 minutes
and 30 polimerization cycles (95-C for 30 seconds, 50Y60-C
for 20 seconds, and 60-C for 4 minutes, depending on the
exons studied). The PCR products were purified in Centri Sep
columns (PE) and then were subjected to electrophoresis in
5% polyacrylamide gel (Long Ranger) with 8-mol/L urea for
7 hours, 2.4 kV in ABI PRISM 377 sequenator (PE).
Statistical Analysis
The associations between categorical variables were
determined using W2 test (Yates correction) and SYSTEM
MEDISTAT ver. 1.0 statistical program. P G 0.05 was con-
sidered to indicate statistical significance.
RESULTS
Molecular Results
Mutations in TP53 gene were detected in 27 of the 81
endometrial cancers (33.3%). In 3 cases, 2 different muta-
tions developed simultaneously. Altogether in the studied
cancers, 30 (37.0%) TP53 gene mutations were identified.
The mutations detected in TP53 gene were located in exons
4 to 8 and 10. Among the mutations identified, 28 were mu-
tations of single nucleotide exchange type, which in 26
cases led to exchange of amino acids in the encoded protein,
whereas 2 mutations were silent. In 12 cancers, Cys242Ser
mutation was present. In 6 cancers, Lys351Met mutation was
found. Four other cancers had Thr253Pro (2 cases) and
Gly302Trp (2 cases) mutations. The remaining 6 mutations of
single nucleotide exchange type were found in isolated cases.
Besides that, one 27-base pair (bp) deletion from codons 193
to 201 in exon 6 was detected with consequent falling out of
9 amino acids, and one A679 insertion in exon 7 was found
leading to protein synthesis discontinuation in codon 228. A
detailed description of all mutations detected in TP53 gene
is contained in Table 1. The location of the mutations found
within TP53 is presented in Figure 1.
Mutations in PTEN gene were detected in 39 cancers
(39/81 [48.1%]). In 6 cancers, 2 different mutations in PTEN
gene were identified simultaneously. Altogether, 45 PTEN mu-
tations (55.5%) were found in the studied cancers (Table 2).

FIGURE 1. Localization of mutations in TP53 gene sequence in endometrial cancers. Numbers over symbols indicate
numbers of codons; %, frequency of mutations; E1YE11, numbers of exons.

198 * 2010 IGCS and ESGO

Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
International Journal of Gynecological Cancer & Volume 20, Number 2, February 2010 TP53 and PTEN Mutations

TABLE 2. Correlations between mutations in TP53 and PTEN genes and clinicopathological features
of endometrial cancers
Mutations
TP53* PTEN
Clinicopathological
Data n (%) P† n (%) P†
Patient age, yr‡
G55 7/21 (33.3) 0.890 16/21 (76.2) 0.027
Q55 21/60 (35.0) 29/60 (48.3)
Type of cancer
Endometrioid 28/81 (34.6) 45/81 (55.5)
FIGO clinical stage
IA 10/28 (35.7) 0.369 (IAYC vs II + III) 14/28 (50.0) 0.950 (IAYC vs II + III)
IB 10/24 (41.7) 12/24 (50.0)
IC 4/13 (30.8) 10/13 (76.9)
II 0/4 (00.0) 3/4 (75.0)
III 4/12 (33.3) 6/12 (50.0)
Histological grade
G1 12/33 (36.4) 0.778 (G1 vs G2 + G3) 14/33 (42.4) 0.049 (G1 vs G2 + G3)
G2 8/32 (25.0) 23/32 (71.9)
G3 8/16 (50.0) 8/16 (50.0)
*Without 2 silent mutations.
†P G 0.05 was considered significant (W2 test [Yates correction]).
‡Ages of premenopausal (G55) and postmenopausal (Q 55) patients were used as cutoff point.

The mutations found showed a considerable diversity and de-
veloped in exons 1 to 5 and 7 to 8. Detailed descriptions of
PTEN mutations we detected in endometrial cancers are con-
tained in our earlier articles.7 The locations of PTEN mutations
in endometrial cancers are presented in Figure 2.
Coexistence of TP53 and PTEN Gene
Mutations in Tumors and Their Relations
With Clinicopathological Features
In 64.2% of cases, mutations occurred in TP53 and/or
PTEN genes, including mutations only in TP53 gene in
16.1% of cases and only in PTEN gene in 33.3%. In 14.8%
of cancers, simultaneous mutations were in TP53 and PTEN
genes, and in 35.8%, no mutations were detected in these
genes (Table 3). No statistically significant relationship was
found between the incidence of mutations in TP53 and that
in PTEN genes (P = 0.986).
The relationship between the presence of mutations
(2 silent-type mutations were rejected) in TP53 and PTEN
genes and the selected clinicohistopathological parameters
is presented in Table 2. The changes in PTEN gene occurred
significantly more frequently in younger patients (G55 years)
than in older women (Q55 years); P = 0.027. On the other

FIGURE 2. Localization of mutations in PTEN gene sequence in endometrial cancers. Numbers over symbols
indicate numbers of codons; %, frequency of mutations; E1YE9, numbers of exons.

* 2010 IGCS and ESGO 199

Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
Janiec-Jankowska et al International Journal of Gynecological Cancer
TABLE 3. Coexistence of mutations in TP53 and PTEN
genes in endometrial cancers
Group of Cancers
TP53+ TP53j TP53+ TP53j
PTEN+ PTEN+ PTENj PTENj
Endometrial 12/81 27/81 13/81 29/81
cancers (14.8%) (33.3%) (16.1%) (35.8%)
hand, no difference was found between the age of endome-
trial cancer development and the incidence of mutations in
TP53 gene.
In the case of both TP53 and PTEN, no statistically
significant relationship was observed between the incidence
of mutations in these genes and the clinical progression of
cancer according to the FIGO classification.
A statistically significant difference was found between
the incidence of mutations in PTEN gene and the grade of
histological differentiation of cancer. In PTEN gene, the inci-
dence of mutations was more than twice higher in medium
(G2) and poorly (G3) differentiated endometrial cancers than
that in well-differentiated (G1) cancers and was statistically
significant (P = 0.049). In TP53 gene, no similar relationship
was found (P = 0.778).
DISCUSSION
The development of endometrial cancer, as that of any
malignancy, is caused by accumulation of many defects in the
genetic material. Although some changes have been identi-
fied, which are of critical importance for endometrial cancer
development, the molecular mechanisms of carcinogenesis of
this malignancy have not been fully elucidated so far.
Among the genetic lesions identified to date, occurring
in sporadic endometrial cancers, best documented were
mutations in PTEN gene.15 Inactivating mutations of PTEN
were detected in more than a half of endometrial cancers,
mainly of endometrioid type (type 1).4,18 Besides that, they
developed in approximately 20% of endometrial hyperplasia
cases and, in consequence, were considered as precursor
changes in the development of ECs.4 In our present and
previous studies,7 we demonstrated PTEN mutations in 48%
to 55% of cases of endometrial cancer. These data are in
agreement with the reports in the literature, which demonstrate
the incidence of PTEN mutations in endometrial cancers to
be approximately 50% on the average and even almost
80%.4,18Y20 However, in almost half of them, no PTEN gene
mutations are detected, which suggests that other genes are
involved in the pathogenesis of endometrial cancer.
One of them is possibly TP53 gene. The TP53 protein
encoded by this gene is a transcription factor with cancer
suppressor properties. It participates in regulation of numer-
ous cell processes such as activation of DNA repair mecha-
nisms, inhibition of cell growth through cell cycle regulation,
or induction of apoptosis in response to DNA damage.21 The
absence of normally functioning TP53 protein makes pos-
200
Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
& Volume 20, Number 2, February 2010
sible cancer cells to multiplicate the genome damages occur-
ring in them and determines their immortality, which leads to
cell development and into malignancy.18 The mutations oc-
curring in TP53 gene, most frequently lead to overexpression
and TP53 protein cumulation in cell cytoplasm. Germinal
TP53 gene mutations can be transferred in families, among
other things as Li-Fraumeni syndrome.22 Somatic mutations
in TP53 gene belong to the most frequent genetic changes in
human neoplastic cells and are found in almost all types of
tumors.8,21,23
Recent studies suggest a functional connection between
the pathways of TP53 and PTEN genes and the possibility of
cooperation of both genes in cancer development. Stambolic
et al11 demonstrated in their studies that wild TP53 protein
binds directly to PTEN gene promoter and thus activates its
transcription and causes increase of messenger RNA and
PTEN protein levels in the cell. Su et al24 demonstrated that
normal PTEN protein, as active phosphatase, enhances the
function of wild TP53 protein by inhibition of AKT and
MDM2 protein activation. Moreover, Li et al25 proved that
PTEN controls the stabilization of TP53 protein by antago-
nizing, as phosphatase, the AKT-MDM2 pathway and also
by direct interaction with TP53. On the other hand, Levine26
demonstrated that absence or damage of PTEN protein caused
loss of TP53 activity and, in consequence, inability of can-
cer cells to respond to DNA damages in apoptotic way. These
studies show that defects occurring in TP53 or PTEN genes
can lead to loss of function of each of them and contribute to
cancer development.
Undertaking studies on the occurrence of TP53 gene
mutations in endometrial cancer, we intended both to assess
their incidence and to check their relationship with the occur-
rence of mutations in PTEN.
In the present study, we identified altogether 28 poten-
tial pathogenic mutations in TP53 gene (34.6%) in 25 of 81
studied cancers. In 3 cases, 2 different mutations were present
in the same tumor, simultaneously.
Most of the studies conducted to date on the partici-
pation of TP53 gene in endometrial carcinogenesis demon-
strated that changes in this gene were the most characteristic
genetic defects in nonendometrioid, that is, serous and clear
cell endometrial cancers (type 2). TP53 gene mutations and
TP53 protein overexpression occurred in 70% to 85% of
these tumors.3,18,19 The tumors we studied included only en-
dometrioid cancers (type 1) because the aim of the study was
to determine the quality and the frequency of incidence of
TP53 and PTEN gene mutations and to assess their coex-
istence in this type of endometrial cancer.
The role of TP53 in EC is poorly elucidated. However,
it is known that in this most frequently encountered type
of endometrial cancer, TP53 mutations develop in approx-
imately 20% of cases. Koul et al19 demonstrated presence
of mutations in TP53 gene in 17%, Lax3 in 20%, and
Macwhinnie and Monaghan18 in 25% of ECs.
In the present study, mutations in TP53 gene were
found in 30.9% of type 1 cancers. Most TP53 mutations de-
scribed to date occurred in exons 5 to 8, encoding the domain
that binds TP53 protein to DNA.16,17,27 The TP53 mutations
identified in the present study were located in exons 4 to 8 and
* 2010 IGCS and ESGO
International Journal of Gynecological Cancer & Volume 20, Number 2, February 2010
10. Among the mutations identified, 28 were of single nucle-
otide exchange type, which in 26 cases led to amino acid
exchange in the encoded protein, whereas 2 were silent muta-
tions. Besides that, 1 deletion of 27 nucleotides from codons
193 to 201 was identified, leading in consequence to elim-
ination of 9 amino acids from the encoded protein, and 1
insertion of single adenine (A679) was found, leading to ter-
mination of protein synthesis.
Kim et al28 demonstrated that amino acids 112 to 142
and 236 to 251 appearing within the DNA-binding domain of
TP53 protein (amino acids, 102Y292) are responsible for its
binding to DNA. The elimination of the binding activity of
TP53 to DNA due to mutation leads to loss of suppressor
function of TP53. In the cancers we studied, this may include
cases with the following mutations: Cys242Ser, Del 27 bp
from codons 193 to 201, and Ins A in codon 227, and possibly
also cases with the remaining mutations located within the
DNA-binding domain: Thr253Pro, Leu257Met, Cys277Phe,
and Arg280Gly. The studies by other authors29 show that mu-
tations in codons 135 to 175 lead to loss of DNA-binding
ability through contribution to protein conformation change.
The mutation Thr150Ser we found theoretically can cause
such changes in the encoded TP53 protein. On the other hand,
Mateu and Fersht29 demonstrated that some mutations within
the oligomerization domain of TP53 protein (codons 326Y353)
could contribute to loss of its ability to oligomerization and to
penetration of TP53 protein into cell nucleus. Among the mu-
tations we detected, this may concern Lys351Met exchange.
However, the final assessment of the importance of muta-
tions identified in our study can be made only after studying
their biological effects developing at protein level.
Mutation development in TP53 gene is usually con-
nected with aggressive forms of cancer and with shortening
of patients’ survival time, as it is, for example, in breast, large
bowel, or lung cancer.30,31 In type 1 endometrial carcinoma,
TP53 disorders in the form of mutation and overexpression of
encoded protein are detected mainly in morphologically less
differentiated (G3) cases, and they develop significantly less
frequently in highly differentiated cancers (G1).18,32 In our
studies too, TP53 mutations were more frequent in G3 can-
cers (50.0%) than in G1 and G2 tumors (36.4% and 25.0%,
respectively), but these differences were statistically not sig-
nificant, which could have resulted from small number of G3
cancers. The results of these preliminary studies could suggest
that mutations in TP53 gene are a late factor in the carci-
nogenesis of ECs, possibly influencing their progression.
The potential relationship between TP53 gene muta-
tions and changes in other genes, including PTEN, observed
in endometrial cancers is still poorly known. TP53 mutations
usually do not occur with PTEN mutations in the same tumor.
Singh et al33 demonstrated that mutations in TP53 and PTEN
genes excluded each other in head and neck squamous cell
carcinoma. On the other hand, Inaba et al34 demonstrated that
defects of TP53 and PTEN genes developed simultaneously
in the same tumor at late stages of carcinogenesis and oc-
curred independently of each other in early endometrial can-
cers. Our studies showed that 14.8% of endometrial cancers
had simultaneous TP53 and PTEN mutations in the same
tumor, which could suggest their common pathway in carci-
* 2010 IGCS and ESGO
Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
TP53 and PTEN Mutations
nogenesis. In our study, we demonstrated that in 16.1% of
cases, mutations in TP53 gene were present independently of
mutations in PTEN gene. Another part of the studied tumors
(33.3%) had PTEN mutations, without mutations in TP53
gene. In 35.8% of cases, no mutations were detected in either
studied gene.
The results of this study confirm our previous obser-
vations that PTEN gene mutations play a key role in endo-
metrial carcinogenesis. Moreover, the results of the study
demonstrate that TP53 gene mutations occur in some of
ECs in the presence of PTEN gene mutations, which sug-
gests that both these genes participate in the development of
these tumors.
The testing for PTEN and TP53 genes can be a good
clinical indicator of tumor progression and of the risk of
endometrial cancer development.
ACKNOWLEDGMENT
The authors thank the investigator, C. Goluda (Clinic
of Gynaecology, Medical Academy, Wroclaw, Poland), who
participated in the study by contributing case and control
samples.
REFERENCES
1. Didkowska J, Wojciechowska U, Tarkowski W, et al. Nowotwory
zaovliwe w Polsce w 2003 roku. Warszawa, Centrum
Onkologii-Instytut im. M. Skaodowskiej-Curie; 2005.
2. Bockman JV. Two pathogenetic types of endometrial carcinoma.
Gynecol Oncol. 1983;15:10Y17.
3. Lax SF. Molecular genetic pathways in various types of
endometrial carcinoma: from a phenotypical to a
molecular-based classification. Virchows Arch. 2004;444:
213Y223.
4. Risinger JI, Hayers K, Maxwell GL, et al. PTEN mutations in
endometrial cancer is associated with favorable clinical and
pathologic characteristics. Clin Cancer Res. 1998;4:
3005Y3010.
5. Berchuck A, Rodriguez G, Kinney RB, et al. Overexpression of
HER-2/neu in endometrial cancer is associated with advanced
stage disease. Am J Obstet Gynecol. 1991;164:15Y21.
6. Liu FS. Molecular carcinogenesis of endometrial cancer. Taiwan
J Obstet Gynecol. 2007;46:26Y32.
7. Konopka B, Janiec-Jankowska A, Paszko Z, et al.
The coexistence of ERBB2, INT2, and CMYC oncogene
amplifications and PTEN gene mutations in endometrial
carcinoma. J Cancer Res Clin Oncol. 2004;130:114Y121.
8. Harris CC. Structure and function of the p53 tumor suppressor
gene: clues for rational cancer therapeutic strategies. J Natl
Cancer Inst. 1996;88:1442Y1455.
9. Soyoola EO, Pattillo RA. PTEN/MMAC1 mutations correlate
inversely with an altered p53 tumor suppressor gene in
gynecologic tumors. Am J Obstet Gynecol. 2003;188:33Y36.
10. Tang Y, Eng Ch. PTEN autoregulates its expression by
stabilization of p53 in phosphatase-independent manner.
Cancer Res. 2006;66:736Y742.
11. Stambolic V, MacPherson D, Sas D, et al. Regulation of
PTEN transcription by p53. Mol Cell. 2001;8:317Y325.
12. Oki E, Tokunaga E, Nakamura T, et al. Genetic mutual
relationship between PTEN and p53 in gastric cancer. Cancer
Lett. 2005;227:33Y38.
201
Janiec-Jankowska et al International Journal of Gynecological Cancer
13. Creasman WT. Revision in classification by International
Federation of Gynecology and Obstetrics. Am J Obstet Gynecol.
1992;167:857Y858.
14. Scully RE, Bonfiglio TA, Kurman RJ. Histological Typing
of Female Genital Tract Tumors, in WHO: International
Histological Typing of Tumors. New York: Springer; 1994:
14Y31.
15. Risinger JI, Hayers AK, Berchuck A, et al. PTEN/MMAC1
mutations in endometrial cancers. Cancer Res. 1997;37:
4736Y4738.
16. Buchman VL, Chumakov PM, Ninkina NN, et al. A variation in
the structure of the protein-coding region of the human p53
gene. Gene. 1988;70:245Y252.
17. Sakuragi S, Salah-Eldin A, Watari H, et al. Bax, bcl-2, and
p53 expression in endometrial cancer. Gynecol Oncol. 2002;
86:288Y296.
18. Macwhinnie N, Monaghan H. The use of P53, PTEN, and
C-erbB-2 to differentiate uterine serous papillary carcinoma
from endometrioid endometrial carcinoma. Int J Gynecol
Cancer. 2004;14:938Y946.
19. Koul A, Willen R, Bendahl PO, et al. Distinct sets of gene
alterations endometrial carcinoma implicate alternate modes
of tumorigenesis. Cancer. 2002;94:2369Y2379.
20. Krbo A, Kaino T, Arnes M, et al. Genetic derangements in the
tumor suppressor gene PTEN in endometrial precancers as
prognostic markers for cancer development: a population-based
study from northern Norway with long-term follow-up.
Gynecol Oncol. 2004;95:82Y88.
21. Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene.
2003;22:9030Y9040.
22. Varley JM. Germline TP53 mutations and Li-Fraumeni
syndrome. Hum Mutat. 2003;21:313Y316.
23. De Witte HH, Foekens JA, Lennerstrand J. Prognostic
significance of TP53 accumulation in human primary breast
cancer: comparison between a rapid quantitative immunoassay
and SSCP analysis. Int J Cancer. 1996;69:125Y133.
24. Su JD, Mayo LD, Donner BD, et al. PTEN and
202
Copyright @ 2010 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.
& Volume 20, Number 2, February 2010
phosphatidylinositol 3¶-kinase inhibitors up-regulate p53 and
block tumor-induced angiogenesis: evidence for an effect on
the tumor and endothelial compartment. Cancer Res. 2003;
63:3585Y3592.
25. Li AG, Piluso LG, Cai X, et al. Mechanistic insights into
maintenance of high p53 acetylation by PTEN. Mol Cell.
2006;23:575Y587.
26. Levine AJ. p53, the cellular gatekeeper for growth and division.
Cell. 1997;88:323Y331.
27. Elmasry K, Gayther SA. Genetic mutations in gynaecological
cancers. Rev Gynaecol Perinat Pract. 2006;6:115Y125.
28. Kim HJ, Song ES, Hwang TS. Higher incidence of p53
mutation in cervical carcinomas with intermediate-risk HPV
infection. Eur J Obstet Gynecol Reprod Biol. 2001;98:
213Y218.
29. Mateu MG, Fersht AR. Nine hydrophobic side chains
are key determinants of the thermodynamic stability and
oligomerisation status of tumour suppressor p53 tetramerization
domain. EMBO J. 1998;17:2748Y2758.
30. Powell B, Soong R, Iacopetta B. Prognostic significance of
mutations to different structural and functional regions of
the p53 gene in breast cancer. Clin Cancer Res. 2000;6:
443Y449.
31. Lea IA, Jackson MA, Li X, et al. Genetic pathways and
mutation profiles of human cancers: site- and exposure-specific
patterns. Carcinogenesis. 2007;28:1851Y1858.
32. Kushi AA, Lim P, Aquino-Parsons C, et al. Markers of
proliferative activity are predictors of patient outcome for
low-grade endometrioid adenocarcinoma but not papillary
serous carcinoma of endometrium. Mod Pathol. 2002;15:
365Y371.
33. Singh B, Reddy PG, Goberdhan A, et al. p53 regulates cell
survival by inhibiting PIK3CA in squamous cell carcinomas.
Genes Dev. 2002;16:984Y993.
34. Inaba F, Kawamat H, Teramoto T, et al. PTEN and p53
abnormalities are indicative and predictive factors for
endometrial carcinoma. Oncol Rep. 2005;13:17Y24.
* 2010 IGCS and ESGO