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A Genomic Diagnostic Tool For Human Endometrial Receptivity Based On The Transcriptomic Signature
A Genomic Diagnostic Tool For Human Endometrial Receptivity Based On The Transcriptomic Signature
Objective: To create a genomic tool composed of a customized microarray and a bioinformatic predictor for en-
dometrial dating and to detect pathologies of endometrial origin. To define the transcriptomic signature of human
endometrial receptivity.
Design: Two cohorts of endometrial samples along the menstrual cycle were used: one to select the genes to be
included in the customized microarray (endometrial receptivity array [ERA]), and the other to be analyzed by
ERA to train the predictor for endometrial dating and to define the transcriptomic signature. A third cohort includ-
ing pathological endometrial samples was used to train the predictor for pathological classification.
Setting: Healthy oocyte donors and patients.
Patient(s): Healthy fertile women (88) and women with implantation failure (5) or hydrosalpinx (2).
Intervention(s): Human endometrial biopsies.
Main Outcome Measure(s): The gene expression of endometrial biopsies.
Result(s): The ERA included 238 selected genes. The transcriptomic signature was defined by 134 genes. The
predictor showed a specificity of 0.8857 and sensitivity of 0.99758 for endometrial dating, and a specificity of
0.1571 and a sensitivity of 0.995 for the pathological classification.
Conclusion(s): This diagnostic tool can be used clinically in reproductive medicine and gynecology. The transcrip-
tomic signature is a potential endometrial receptivity biomarkers cluster. (Fertil Steril 2011;95:50–60. 2011 by
American Society for Reproductive Medicine.)
Key Words: Endometrial receptivity, endometrial dating, microarray, transcriptomic signature, predictor,
diagnostic tool
The endometrium is a highly dynamic tissue with the capacity to un- morphological features of the different compartments of the
dergo physiological changes in response to steroid hormones with endometrium throughout the menstrual cycle. These classic
the ultimate aim of creating a receptive status in a synchronized articles have been widely quoted, and followed as ‘‘the diagnostic
manner with the arrival of the implanting blastocyst during the win- tool’’ for endometrial dating. However, their accuracy and
dow of implantation (WOI) between days 19 and 21. functional relevance as a predictor of endometrial receptivity have
For more than 60 years histologic evaluation has been considered been questioned in randomized studies (3, 4).
a standard for clinical diagnosis based on morphological observa- During the WOI, the endometrium displays a receptive pheno-
tions (1, 2). Noyes and collaborators (1, 2) described ‘‘specific’’ type. At the morphological level, the endometrial epithelial cells
undergo plasma membrane transformation (5), with pinopodes
Received October 30, 2009; revised April 19, 2010; accepted April 26, that have been proposed to be the makers of morphological receptive
2010; published online July 8, 2010. status (6). However, their functional role is questionable (7).
P.D.-G. has nothing to disclose. J.A.H. has nothing to disclose. J.A.M.-C. Other methods have been presented as alternatives to the classic
has nothing to disclose. F.J.E. has nothing to disclose. P.A. has nothing
Noyes criteria such as biochemical markers (8), hormones receptors
to disclose. A.P. has nothing to disclose. C.S. has nothing to disclose.
Patricia Dıaz-Gimeno and Jose A. Horcajadas contributed equally to this (9, 10), and immunohistochemical detection of biomarkers (11–13).
work. However, they have not been consolidated as diagnostic tools (14).
Supported by grants SAF2004-00204 and SAF2008-04349 from the With the arrival of microarray technology (15), the number of
Spanish Government (P.D.-G.). Patricia Dıaz is a predoctoral fellow possible targets has increased substantially, and the functional
supported by the Programa para la Formacio n de Personal Investiga- genomics of endometrial receptivity has been widely investigated
dor de la Generalitat Valenciana (BFPI). in the past 7 years in natural cycles (16–20), controlled ovarian
Presented at the 64th Annual Meeting of the American Society for
stimulation (COS) cycles (21–23), and refractory cycles (24) (see
Reproductive Medicine, San Francisco, CA, November 8–12, 2008.
Reprint requests: Jose A. Horcajadas, Ph.D., C/ Catedra
tico Agustın Escardino Ref. 25 for review). At present, in today’s genomic era with the de-
n 9, Edificio 2-BIOTEC, Laboratorio 2.07, 46980 Paterna (Valencia), Spain velopment of sophisticated bioinformatic information technologies,
(FAX: 34-963-383-181; E-mail: jhorcajadas@igenomix.net). new perspectives of the analysis and classification of subclasses of
No. of
Gene symbol Gene name Fold change probes
No. of
Gene symbol Gene name Fold change probes
52 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
TABLE 1
Continued.
No. of
Gene symbol Gene name Fold change probes
No. of
Gene symbol Gene name Fold change probes
54 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
TABLE 1
Continued.
No. of
Gene symbol Gene name Fold change probes
the disease emerge, especially tumor classification (26–28) and define the receptivity gene expression signature. Endometrial biopsies from
complex functions (29, 30) such as endometrial receptivity. a pathological condition were used to train for the pathological classification.
The aim of this study is to develop a customized endometrial
receptivity array (ERA) and to define the transcriptomic signature Endometrial Tissue Collection
for human endometrial receptivity. To prove its translational effi- This study was approved by the Ethics Committee of the Instituto Valenciano
ciency, we designed a bioinformatic test with predictive power to de Infertilidad, Valencia, Spain. Written informed consent was obtained from
classify the human endometrium gene expression profile that is all the patients.
compatible with LHþ7 and to detect the endometrial disorders The endometrial samples for the ERA gene selection (n ¼ 20, gene selec-
relating to it. tion set) were a prereceptive group LHþ1, LHþ3, LHþ5, and a receptive
group LHþ7 (five in each LH day), samples were collected and used in
our study (31).
MATERIALS AND METHODS Endometrial samples to train the predictor to date the endometrium and to de-
fine the transcriptomic signature (n ¼ 68, training set) were obtained from fer-
The ERA Gene Selection tile women during their menstrual cycle, and were classified as receptive (R),
To select the genes involved in human endometrial receptivity as candidates prereceptive (PR), or proliferative (P). Group R was represented by those sam-
to be included in the ERA, we analyzed the different gene expression profile ples taken on day LHþ7 (days 20–21 of the menstrual cycle) (n ¼ 40); in the PR
in the entire human genome between the receptive and the prereceptive group, samples were collected on days LHþ1 to LHþ5 (n ¼ 13); the P group
endometrium (gene selection set) using the raw expression data from our samples were collected on days 8–12 of the menstrual cycle (n ¼ 15). To train
previous work (31). We performed a t-test and the genes showing an absolute the predictor for the pathological classification endometrial biopsies from pa-
fold-change >3 and a false discovery rate <0.05 were selected. We used tients with pathological conditions (PH) were also collected at LHþ7 (implan-
three statistical approaches: the union of the T-Rex gene list (GEPAS) tation failure [n ¼ 5] and hydrosalpinx [n ¼ 2]). Seven endometrial samples,
http://gepas.bioinfo.cipf.es/) and the SAM gene list (http://www.stat.stanford. which belonged to the different groups, were excluded for technical reasons.
edu/tibs/SAM/), intersected with the multtest gene list (http://www.biocon Endometrial biopsies were collected as previously described (31). The LH
ductor.org/). Mathematically it can be written as: [T-Rex U SAM] X multtest. measurement was performed by assessing the serum LH levels on a daily basis.
The ERA gene dose during the menstrual cycle To analyze the behav-
ior of the ERA gene expression throughout the menstrual cycle, MaSigPro
(35) of the GEPAS Suite CIPF, Valencia, Spain (36) was used to analyze
the profile differences in the training set.
RESULTS
The ERA Gene Selection
In total, 238 genes were found to be differentially expressed at the re-
ceptive phase (Table 1). These genes were included in the ERA and
were represented by 569 existing probes (Supplemental Table 2,
available online). Finally, 536 other Agilent internal controls were
included.
56 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
FIGURE 2
Gene clustering of ERA genes. Proliferative phase is named as 7 (day 7), prereceptives as 14 (day 14), and receptive as 21 (day 21). Gene
number belonging to each cluster is indicated at the bottom of the graphic.
immune response, innate immune response, and response to wound- The ERA Gene Dose During the Menstrual Cycle
ing. Other biological processes were circulation, response to external The clustering of the ERA genes was carried out to detect the genes
stimulus, behavior, cell cycle, cell adhesion, anatomical structure de- with similar behavior from the proliferative to the midsecretory
velopment, cell–cell signaling, and the mitotic cell cycle. In the MF phases. The nine most representative clusters detected for these
section, three terms were over-represented: oxidoreductase activity, genes are shown in Figure 2. A proliferative endometrium was coded
carbohydrate binding, and receptor binding. In the third section, CC, d7, the pre-receptive one was coded d14, and a receptive one was
the spindle and spindle microtubule were over-represented. coded d21 in the clusters. Cluster 1 was represented by 50 genes
whose gene expression from the proliferative to the prereceptive
phase was lower, showing a sharp increase at the receptive phase
Clustering Sample Analysis
(Fig. 2). Cluster 7, with 37 genes, also increased sharply at the recep-
The clustering analysis of the training set generated two very well- tive phase with an irrelevant transition from the proliferative to the
defined groups (Fig. 1). The samples grouped as ‘‘receptive’’ in- prereceptive phase. On the other hand, cluster 5 was formed by 72
cluded samples of group R (n ¼ 40), whereas the ‘‘nonreceptive’’ genes, which down-regulated in the receptive phase. The other clus-
ones included samples of the PR and P groups (n ¼ 28), which is ters showed less pronounced differences in expression terms among
in agreement with a pre-existing prognostic signature. the different menstrual cycle phases.
the first comparison, 200 genes (110 up-regulated and 90 down- DISCUSSION
regulated) were statistically differentially expressed as were 179 In reproductive medicine, an important challenge is to objectively
genes (93 up-regulated and 86 down-regulated) in the second one identify and diagnose the endometrial receptivity status during the
(Fig. 3A). The intersection between both generated a list of 134 WOI. This study centers first on creating a molecular tool using
(74 up-regulated and 60 downregulated) statistically differentially microarray technology (ERA), and second, on determining the
expressed genes between R and the other two classes (PR and P) transcriptomic signature of the endometrium during the WOI. In
(Fig. 3A). These genes are labeled with an asterisk in the column our latest publication (31) we reported two well-differentiated
gene symbol of Table 1. The t-statistic values of these genes are rep- gene expression profiles during the development of the luteal phase
resented in Figure 3B in decreasing order. The t-statistic values of in natural cycles: prereceptive and receptive. In the current work and
these genes are shown in Supplemental Table 4 (available online). using robust and strict selection criteria, 238 genes have been shown
to be differentially expressed in the transition from the prereceptive
Predictor status to the receptive status (Table 1). The proportion of the
The best result for prediction in all cases was obtained with SVM. up-regulated and down-regulated genes found in this selection are
The results for the endometrial dating indicated an ACC of 95% in agreement with the fact that endometrial receptivity is a ‘‘tran-
and an AUC of 0.94, with a specificity and sensitivity of 0.8857 scriptional awakening process,’’ a term previously coined by our
and 0.99758, respectively. group (31).
For the pathological classification the results revealed an ACC of We compared this list with the 25 gene targets proposed in 2007
87% and an AUC of 0.57 with a specificity and sensitivity of 0.1571 (25), and we found that 18 of the 25 gene targets were included in the
and 0.995, respectively. ERA design, which was prepared using an independent selection
58 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
method. These consensus genes are indicated in bold in Table 1. generated by the double comparison between R versus PR and R
Furthermore, we compared our selection with a recent microarray versus P (Fig. 3A) to isolate those genes exclusively expressed
designed with 126 genes for the diagnosis of endometrial disorders during the WOI.
(45), and found that 61 genes are included in both designs. The list This work mainly focuses on creating a molecular tool for clinical
also contains two genes that have been recently published as new use to objectively diagnose the endometrial receptivity status. In our
potential biomarkers of human endometrial receptivity, such as study, the endometrial dating attempts to classify an LHþ7 endome-
laminin b3 and microfibril-associated protein 5 (46). trium (R) in transcriptomic terms with a specificity and sensitivity of
The functional analysis by gene ontology of the ERA reveals 0.8857 and 0.99758, respectively. These results show the diagnostic
the biological sense of the ERA selection. The most significant an- power of this molecular tool for endometrial dating.
notation is the presence of several BP relating to the immune re- For the pathological classification used to discriminate between
sponse whose implication in embryo implantation has been physiological and pathological conditions, the numbers are low
previously reported (47, 48). Another BP of interest is the and unbalanced given the difficulty in obtaining such samples.
cytoskeleton proteins needed for remodeling the endometrium Nonetheless, we expect to be able to include more samples to better
during the WOI. Regarding MF, there are three different terms in define the profiles in the near future, and it is possible that more than
the MF4 category that appear as over-represented: oxidoreductase one profile will arise in this group. In any case, the clinical relevance
activity, carbohydrate binding, and receptor binding. All three are of the second model resulted in the nondetection of false-positive re-
relevant activities involved in cell adhesion, signal transduction, sults in the normal samples, which means that none of the normal
and other functions that are supposedly crucial in embryonic im- samples is classified as pathological.
plantation. Finally in the section CC, only one term is represented This is the first time that a molecular tool based on microarray
at two different levels, CC10 and CC11, spindle and spindle micro- technology can be used clinically in reproductive medicine to eval-
tubules, which mainly relate with the mitotic cycle and cellular uate the endometrium. This genomic tool (ERA þ predictor) is
proliferation. a unique innovative and objective procedure for clinical endometrial
The clustering of training set samples into two well-defined evaluation that will probably improve endometrium-related evalua-
groups (Fig. 1) is in agreement with previous works (49, 50) and tions and diagnoses. The ERA is also a new molecular research tool
they confirm proper gene selection. By doing this clustering, we for endometrial research as it contains a finite number of genes in-
also tested that no other covariable was present by which samples volved in endometrial receptivity, thus avoiding the use of whole ge-
could be grouped. Therefore, both gene selection and sample nome microarrays, which cuts down on costs and simplifies the data
selection seem to have been correctly chosen. analysis. Furthermore, the methodology presented herein could
We also analyzed the gene expression profile of the ERA genes in serve to inspire new molecular approaches for diagnoses or evalua-
the proliferative, prereceptive, and receptive phases. This gene dose tions, and to also switch from anatomical to molecular medicine.
confirmed the presence of groups of genes that were up-regulated
(clusters 1 and 5) and down-regulated (cluster 7) and differently ex- Acknowledgments: The authors thank Ignacio Medina for his help in the bio-
pressed (Fig. 2), which could classically could be used as endome- informatics analysis, to Sebastian Martınez and Alicia Qui~nonero for their
trial receptivity biomarkers. However, we defined the endometrial technical support as well as the medical staff of IVI for their collaboration
receptivity transcriptomic signature by using the 134 ERA genes in the sample collection. Finally, our thanks also go to Fundacion IVI.
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8. Giudice LC, Saleh W. Growth factors in Quantitative monitoring of gene expression patterns Gene expression profiles and structural/functional
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60 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
SUPPLEMENTAL FIGURE 1
The RT-PCR validation for the ERA genes: GPx3, FDYX2, SPP1, and MT1G. Blue bars indicate fold change in microarray data and red bars
indicate fold change by RT-PCR. GPx3 ¼ glutathione peroxidase 3; FDYX2 - FXYD ¼ domain containing ion transport regulator 2; SPP1 ¼
secreted phosphoprotein 1; MT1G ¼ metallothionein 1G.
140 200
180
120
160
100 140
120
Fold Change
Fold Change
80
100
60
80
40 60
40
20
20
0 0
LH+7/LH+2 LH+7/D8 LH+7/D9 LH+7/D10 LH+7/D11 LH+7/D14 LH+7/LH+2 LH+7/D8 LH+7/D9 LH+7/D10 LH+7/D11 LH+7/D14
Days Days
Gene MT1G
Gene SPP1 35
30
30
25
25
20
Fold Change
20
Fold Change
15
15
10
10
5
5
0
0
LH+7/LH+2 LH+7/D8 LH+7/D9 LH+7/D10 LH+7/D11 LH+7/D14
LH+7/LH+2 LH+7/D8 LH+7/D9 LH+7/D10 LH+7/D11 LH+7/D14
Days Days
ERA Data RT_PCR Data ERA Data RT_PCR Data
60.e2 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
SUPPLEMENTAL TABLE 2
Agilent probe sequences for the ERA genes.
60.e4 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
SUPPLEMENTAL TABLE 2
Continued.
60.e6 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
SUPPLEMENTAL TABLE 2
Continued.
60.e8 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
SUPPLEMENTAL TABLE 2
Continued.
60.e10 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
SUPPLEMENTAL TABLE 2
Continued.
60.e12 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
SUPPLEMENTAL TABLE 3
The gene ontology (GO) analysis of the ERA genes by using FatiGO (40).
Immune response BP3 14.94 26 DPP4 OPRK1 C3 CRISP3 HLA-DOB C4BPA NR4A2 XCL2 LIF CXCL14 4,14E-04
(GO: 0006955) GZMA XCL1 CXCL13
KLRC1 IL15 INDO CD7 BCL6 SERPING1 CLU CTSW GBP2 PSMB10
DEFB1 CFD ARHGDIB
Response to stress BP3 15.52 27 ADRA2A C3 PROS1 AOX1 C4BPA HPSE DUOX1 SOD2 FGB SCYE1 9,49E-03
(GO:0006950) CXCL14 MAP2K6
RAD54B THBD CXCL13 BARD1 IDH1 ANG BCL6 GPX3 GADD45A
SERPING1 CLU
PPARGC1A PENK CFD CDC2
Defense response BP3 10.34 18 C3 AOX1 CRISP3 C4BPA HPSE SCYE1 CXCL14 GNLY CXCL13 IL15 9,76E-03
(GO:0006952) CD7 BCL6 SERPING1
CLU OFD1 DEFB1 PENK CFD
Circulation BP3 4.60 8 EDNRB FGB XCL2 CYP2J2 S100A1 SERPING1 EDN3 TH 9,76E-03
(GO:0008015)
Response to external BP3 10.34 18 C4BPA HPSE FGB XCL2 SCYE1 CXCL14 THBD XCL1 CXCL13 BCL6 9,76E-03
stimulus SERPING1 CLU
(GO:0009605) PPARGC1A DEFB1 CFD C3 PROS1 AOX1
Behavior BP3 6.32 11 OPRK1 XCL2 SCYE1 CXCL14 XCL1 CXCL13 MAOA TRH TH DEFB1 3,36E-02
(GO:0007610) PENK
Cell cycle BP3 12.07 21 HRASLS3 RASSF2 MAP2K6 RAD54B CCNB2 GAS1 PBK BARD1 G0S2 3,59E-02
(GO:0007049) HPGD KIF11 PRC1
ASPM GADD45A IGF2 RPRM DLG7 CORO1A BUB1B CDC2 CDC20
Cell adhesion BP3 10.34 18 CRISP3 MUC16 HABP2 CTNNA2 CLDN10 EMCN BCL6 CLDN4 VCAM1 4,18E-02
(GO:0007155) COBL COMP
AMIGO2 THBS2 POSTN SPP1 LAMB3 COL16A1 ARHGDIB
Anatomical structure BP3 2.41 39 POSTN ID4 EVC OLFM1 SPP1 EDN3 LAMB3 TH CRABP2 NR4A2 4,52E-02
development NDRG2 DUOX1 EDNRB
(GO:0048856) ALPL EFNA1 IGFBP1 CDA TAGLN LIF HAND2 ADAMTS1 PRKCQ
CTNNA2 ENPEP CXCL13
DKK1 LRP4 ANG HEY2 IER3 IL15 EMCN BCL6 CSRP2 HEY1 COBL
COMP IGF2 MSX1
Humoral immune BP4 6.02 10 C3 C4BPA NR4A2 XCL1 KLRC1 SERPING1 CLU PSMB10 DEFB1 CFD 7,06E-03
response
(GO:0006959)
Cell–cell signaling BP4 13.25 22 OPRK1 SLC1A1 HSD11B2 NR4A2 GDF15 EFNA1 XCL2 SCYE1 LIF 7,06E-03
(GO:0007267) CXCL14 XCL1 ENPEP
CXCL13 NRG2 MAOA TRH IL15 GABARAPL1 DLG7 EDN3 TH PENK
Innate immune BP4 4.22 7 SERPING1 CLU DEFB1 CFD C3 CRISP3 C4BPA 7,90E-03
response
(GO:0045087)
Mitotic cell BP4 6.63 11 DLG7 CORO1A BUB1B CDC2 CDC20 CCNB2 GAS1 PBK KIF11 PRC1 2,99E-02
cycle ASPM
(GO:0000278)
Response to wounding BP4 8.43 14 C4BPA HPSE FGB SCYE1 CXCL14 THBD CXCL13 BCL6 SERPING1 3,17E-02
(GO:0009611) CLU CFD C3 PROS1 AOX1
Oxidoreductase activity MF3 18.10 21 CBR3 SORD SOD2 IDH1 MAOA KMO CYP2J2 ACADSB INDO 4,49E-02
(GO:0016491) HSD11B2 LEPREL1 LAMB3 AOX1
TH CYBRD1 GPX3 HPGD DHRS3 CYP3A5 CP DUOX1
Carbohydrate binding MF3 9.48 11 ADAMTS1 EMCN FAM59A THBD GALNT12 SERPINA5 HABP2 KLRC1 4,62E-02
(GO:0030246) THBS2 ANG POSTN
receptor binding MF4 16.91 23 FGB EFNA1 XCL2 SCYE1 IGF2 ANG CXCL14 LIF TRH C3 ADAMTS1 1,52E-02
(GO:0005102) EDN3 SPP1 PPARGC1A XCL1GABARAPL1 GDF15 CXCL13 GREM2
NRG2 PENK GAST DKK1
Spindle CC10 30.43 7 CDC2 CDC20 KIF11 PRC1 KIF4A DLG7 BUB1B 9,47E-05
(GO:0005819)
Spindle microtubule CC11 30.77 4 CDC2 KIF11 PRC1 KIF4A 7,29E-04
(GO:0005876)
Dıaz-Gimeno. Customized array for endometrial receptivity. Fertil Steril 2011. Dıaz-Gimeno. Customized array for endometrial receptivity. Fertil Steril 2011.
60.e14 Dıaz-Gimeno et al. Customized array for endometrial receptivity Vol. 95, No. 1, January 2011
SUPPLEMENTAL TABLE 4
Continued.
Endometrial gene
transcriptomic signature t-test statistic
MFAP2 7.95
MGC11242 8.03
SFRP4 8.03
GALNT12 8.13
PRC1 8.42
C10orf3 8.44
CCNB2 8.49
ECM1 8.59
BARD1 8.78
HEY2 8.84
CDC20 8.92
CRABP2 9.15
PBK 9.55
SOX17 9.81
PECI 9.96
CSRP2 10.19