A genomic diagnostic tool for human endometrial ... - Fertility and Sterility

GENETICS A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature Patricia Dıaz-Gimeno, Ph.D.,a,b Jos e A. Horcajadas, Ph.D.,c Jos e A. Martınez-Conejero, Ph.D.,c d a,b Francisco J. Esteban, Ph.D., Pilar Alam a, M.D., Antonio Pellicer, M.D.,a,b and Carlos Sim on, M.D.a,b,e a

Fundaci on IVI-Instituto Universitario IVI, University of Valencia, Valencia; b Instituto de Investigacion, Sanitaria del Hospital Clinico de Valencia, Valencia University, Valencia; c iGenomix, Valencia; d Department of Experimental Biology, University of Jaen, Jaen; and e Centro de Investigacion Principe Felipe, Valencia, Spain

Objective: To create a genomic tool composed of a customized microarray and a bioinformatic predictor for endometrial 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 including 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 transcriptomic 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 undergo physiological changes in response to steroid hormones with the ultimate aim of creating a receptive status in a synchronized manner with the arrival of the implanting blastocyst during the window of implantation (WOI) between days 19 and 21. For more than 60 years histologic evaluation has been considered a standard for clinical diagnosis based on morphological observations (1, 2). Noyes and collaborators (1, 2) described ‘‘specific’’ Received October 30, 2009; revised April 19, 2010; accepted April 26, 2010; published online July 8, 2010. P.D.-G. has nothing to disclose. J.A.H. has nothing to disclose. J.A.M.-C. has nothing to disclose. F.J.E. has nothing to disclose. P.A. has nothing to disclose. A.P. has nothing to disclose. C.S. has nothing to disclose. A. Horcajadas contributed equally to this Patricia Dıaz-Gimeno and Jose work. Supported by grants SAF2004-00204 and SAF2008-04349 from the Spanish Government (P.D.-G.). Patricia Dıaz is a predoctoral fellow n de Personal Investigasupported by the Programa para la Formacio dor de la Generalitat Valenciana (BFPI). Presented at the 64th Annual Meeting of the American Society for Reproductive Medicine, San Francisco, CA, November 8–12, 2008. A. Horcajadas, Ph.D., C/ Catedra tico Agustın Escardino Reprint requests: Jose n 9, Edificio 2-BIOTEC, Laboratorio 2.07, 46980 Paterna (Valencia), Spain (FAX: 34-963-383-181; E-mail: [email protected]).

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morphological features of the different compartments of the endometrium throughout the menstrual cycle. These classic articles have been widely quoted, and followed as ‘‘the diagnostic tool’’ for endometrial dating. However, their accuracy and functional relevance as a predictor of endometrial receptivity have been questioned in randomized studies (3, 4). During the WOI, the endometrium displays a receptive phenotype. At the morphological level, the endometrial epithelial cells undergo plasma membrane transformation (5), with pinopodes that have been proposed to be the makers of morphological receptive status (6). However, their functional role is questionable (7). Other methods have been presented as alternatives to the classic Noyes criteria such as biochemical markers (8), hormones receptors (9, 10), and immunohistochemical detection of biomarkers (11–13). However, they have not been consolidated as diagnostic tools (14). With the arrival of microarray technology (15), the number of possible targets has increased substantially, and the functional genomics of endometrial receptivity has been widely investigated in the past 7 years in natural cycles (16–20), controlled ovarian stimulation (COS) cycles (21–23), and refractory cycles (24) (see Ref. 25 for review). At present, in today’s genomic era with the development of sophisticated bioinformatic information technologies, new perspectives of the analysis and classification of subclasses of

Fertility and Sterility Vol. 95, No. 1, January 2011 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.

0015-0282/$36.00 doi:10.1016/j.fertnstert.2010.04.063

TABLE 1 List of 238 selected genes for the ERA.

Gene symbol GPX3a,b,c PAEPb,c

COMPc SLC1A1c LIFb TCN1c CXCL14c C4BPAc TSPAN8c LAMB3c MAOAc SOD2c GADD45Ac MUC16 THBDc NNMTc DPP4b,c SCGB2A2c S100Pc SNX10c CPc G0S2 C4.4Ac ANGc ABCC3c XCL1 ADRA2A EFNA1 KLRC1 TAGLNb SLC15A1 IGFBP1 PTGER2 THBS2 HPSEc SERPING1c CFDc CRISP3 C14orf161c RPRMc GASTc EDNRBb,c RARRES1 ABLIM3 GLIPR1 AOX1c CYP3A5 CTSW DHRS3 MYL9 CLUb IER3 GPRC5C C3

Gene name Glutathione peroxidase 3 (plasma) Progestagen-associated endometrial protein (placental protein 14, pregnancyassociated endometrial alpha-2-globulin, alpha uterine protein) (PAEP), transcript variant 2 Cartilage oligomeric matrix protein Solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1 Leukemia inhibitory factor (cholinergic differentiation factor) Transcobalamin I (vitamin B12-binding protein, R binder family) Chemokine (C-X-C motif) ligand 14 Complement component 4 binding protein, alpha Tetraspanin 8 Laminin, beta 3, transcript variant 2 Monoamine oxidase A, nuclear gene encoding mitochondrial protein Superoxide dismutase 2, mitochondrial, nuclear gene encoding mitochondrial protein, transcript variant 2 Growth arrest and DNA damage inducible, alpha Mucin 16, cell surface associated Thrombomodulin Nicotinamide N-methyltransferase Dipeptidylpeptidase 4 (CD26, adenosine deaminase complexing protein 2) Secretoglobin, family 2A, member 2 S100 calcium-binding protein P Sorting nexin 10 Ceruloplasmin (ferroxidase) Putative lymphocyte G0/G1 switch gene GPI-anchored metastasis-associated protein homologue Angiogenin, ribonuclease, RNase A family, 5 ATP-binding cassette, subfamily C (CFTR/MRP), member 3 Chemokine (C motif) ligand 1 Adrenergic, alpha-2A, receptor Ephrin-A1, transcript variant 1 Killer cell lectin-like receptor subfamily C, member 1, transcript variant 2 Transgelin Solute carrier family 15 (oligopeptide transporter), member 1 Insulin-like growth factor-binding protein 1 Prostaglandin E receptor 2 (subtype EP2), 53 kDa Thrombospondin 2 Heparanase Serpin peptidase inhibitor, clade G (C1 inhibitor), member 1, (angioedema, hereditary), transcript variant 1 D component of complement (adipsin) (DF) Cysteine-rich secretory protein 3 Chromosome 14 open reading frame 161 Reprimo, TP53 dependent G2 arrest mediator candidate Gastrin Endothelin receptor type B, transcript variant 2 Retinoic acid receptor responder (tazarotene induced) 1, transcript variant 2 Actin-binding LIM protein family, member 3 GLI pathogenesis-related 1 (glioma) Aldehyde oxidase 1 Cytochrome P450, family 3, subfamily A, polypeptide 5 Cathepsin W Dehydrogenase/reductase (SDR family) member 3 Myosin, light polypeptide 9, regulatory, transcript variant 2 Clusterin (CLU), transcript variant 2 Immediate early response 3, transcript variant long G protein-coupled receptor, family C, group 5, member C, transcript variant 1 Complement component 3

Fold change

No. of probes

35.49 31.43

2 1

30.95 17.57

2 3

15.03 14.76 14.02 13.14 12.90 11.32 9.39 9.06

3 1 2 2 2 1 2 2

8.25 8.01 7.84 7.74 7.72 7.43 6.95 6.56 6.34 6.20 6.03 5.98 5.98 5.80 5.78 5.77 5.75 5.71 5.59 5.35 5.18 5.17 5.17 5.16

1 8 3 2 3 2 1 2 2 2 1 2 1 3 2 3 2 3 2 3 2 3 1 2

5.13 5.09 5.07 5.03 5.00 4.89 4.87 4.87 4.83 4.82 4.82 4.78 4.72 4.72 4.70 4.69 4.69 4.67

2 1 2 3 2 4 1 4 2 2 3 3 1 3 2 4 6 3

Dıaz-Gimeno. Customized array for endometrial receptivity. Fertil Steril 2011.

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TABLE 1 Continued.

Gene symbol AQP3 S100A4c GNLY INDOc NKG7 CORO1A SLPI ARG2c ANXA4c ARID5Bc DEFB1c SPP1a,c DKK1c HABP2b,c GZMA TBC1D2c CDAc C10orf10c SLC38A1 FLJ20152c STAR LMOD1b HAND2 IMPA2b CXCL13c NP DEPDC6c RARRES3c XCL2 MT2Ac TIMP3 RRAS CLDN10 AGR2 PROM1 COTL1 ACTA2 ID4c FAM59A GAS1b FGB LMCD1c SYNE2c TRA@ MRPS2 KCNK7 KRT7c GDF15c MFAP5c IGF2 MT1Ga,c VCAM1 CLDN4c PTPRRc SCYE1 DDX52c

Gene name Aquaporin 3 (Gill blood group) S100 calcium-binding protein A4, transcript variant 1 Granulysin (GNLY), transcript variant NKG5 Indoleamine-pyrrole 2,3 dioxygenase Natural killer cell group 7 sequence Coronin, actin binding protein, 1A Secretory leukocyte protease inhibitor (antileukoproteinase) Arginase, type II, nuclear gene encoding mitochondrial protein Annexin A4 AT-rich interactive domain 5B (MRF1-like) Homo sapiens defensin, beta 1 Secreted phosphoprotein 1 (osteopontin, bone sialoprotein I, early T-lymphocyte activation 1) Dickkopf homologue 1 (Xenopus laevis) Hyaluronan-binding protein 2 Granzyme A (granzyme 1, cytotoxic T-lymphocyte-associated serine esterase 3) TBC1 domain family, member 2 Homo sapiens cytidine deaminase (CDA), mRNA [NM_001785] Chromosome 10 open reading frame 10 Solute carrier family 38, member 1 Hypothetical protein FLJ20152, transcript variant 1 Steroidogenic acute regulator, nuclear gene encoding mitochondrial protein, transcript variant 1 Leiomodin 1 (smooth muscle) Heart and neural crest derivatives expressed 2 Inositol(myo)-1(or 4)-monophosphatase 2 Chemokine (C-X-C motif) ligand 13 (B-cell chemoattractant) Nucleoside phosphorylase DEP domain containing 6 Retinoic acid receptor responder (tazarotene induced) 3 Chemokine (C motif) ligand 2 Metallothionein 2A Tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory) Related RAS viral (r-ras) oncogene homologue Claudin 10, transcript variant 1 Anterior gradient 2 homologue (Xenopus laevis) Prominin 1 Coactosin-like 1 (Dictyostelium) Actin, alpha 2, smooth muscle, aorta Inhibitor of DNA-binding 4, dominant negative helix-loop-helix protein Family with sequence similarity 59, member A Growth arrest-specific 1 Fibrinogen beta chain LIM and cysteine-rich domains 1 Spectrin repeat containing, nuclear envelope 2, transcript variant 5 T-cell receptor alpha locus, mRNA (cDNA clone MGC:70922 IMAGE:5228329), complete cds Mitochondrial ribosomal protein S2, nuclear gene encoding mitochondrial protein Potassium channel, subfamily K, member 7, transcript variant C Keratin 7 Growth differentiation factor 15 Microfibrillar associated protein 5 Insulin-like growth factor 2 (somatomedin A), transcript variant 1 Metallothionein 1G Vascular cell adhesion molecule 1, transcript variant 1 Claudin 4 Protein tyrosine phosphatase, receptor type, R , transcript variant 1 Small inducible cytokine subfamily E, member 1 (endothelial monocyte-activating) DEAD (Asp-Glu-Ala-Asp) box polypeptide 52, transcript variant 2

Fold change

No. of probes

4.63 4.59 4.53 4.49 4.42 4.40 4.39 4.35 4.27 4.19 4.17 4.15

2 2 1 1 1 1 3 1 1 6 2 2

4.10 4.09 4.07 4.07 4.00 3.98 3.97 3.94 3.93

1 2 1 2 2 3 2 2 2

3.92 3.91 3.91 3.90 3.85 3.80 3.79 3.73 3.72 3.71 3.70 3.68 3.67 3.65 3.58 3.58 3.56 3.54 3.53 3.53 3.53 3.52 3.52

2 2 2 3 1 1 1 4 2 2 3 2 1 3 5 2 1 2 2 2 2 6 5

3.49 3.49 3.48 3.47 3.42 3.41 3.41 3.41 3.41 3.40 3.40 3.38

1 2 2 2 2 3 3 1 3 4 2 3


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TABLE 1 Continued.

Gene symbol HAL LEPREL1 ADAMTS1c TH PROS1 EMCN FOSL2c PSMB10 ACADSBc S100A1c AMIGO2c HRASLS3c HMHA1 POLD4c CD7 ARHGDIB LRFN4 GBP2c GABARAPL1c MT1Hc FXYD2a,b,c RNASE4c PPARGC1A CYBRD1 ENPEPc CES1 ATP6V1Ac ASS1 IL15c BCL6c EVC IL2RB EFEMP1 TRHc HLA-DOBb ATP6V0E2c CSRP2c OLFM4c SLC15A2 CALB2 SFRP4c CTNNA2b NR4A2 DUOX1 KIF20Ac PENKc POSTNc LRP4 SLC16A6 GPR64 RANBP17 EDN3c C10orf3c CENPEc KIAA0888 COL16A1c

Gene name Histidine ammonia lyase Leprecan-like 1 A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 1 Tyrosine hydroxylase (TH), transcript variant 3 Homo sapiens protein S (alpha) Homo sapiens endomucin FOS-like antigen 2 Proteasome (prosome, macropain) subunit, beta type, 10 Acyl-coenzyme A dehydrogenase, short/branched chain (ACADSB), nuclear geneencoding mitochondrial protein S100 calcium-binding protein A1 Adhesion molecule with Ig-like domain 2 HRAS-like suppressor 3 Histocompatibility (minor) HA-1 Polymerase (DNA-directed), delta 4 CD7 antigen (p41) Rho GDP dissociation inhibitor (GDI) beta Leucine-rich repeat and fibronectin type III domain containing 4 Guanylate-binding protein 2, interferon-inducible GABA(A) receptor-associated protein-like 1 Metallothionein 1H FXYD domain containing ion transport regulator 2, transcript variant b Ribonuclease, RNase A family, 4, transcript variant 1 Peroxisome proliferative activated receptor, gamma, coactivator 1, alpha Cytochrome b reductase 1 Glutamyl aminopeptidase (aminopeptidase A) Carboxylesterase 1 (monocyte/macrophage serine esterase 1), transcript variant 3 ATPase, Hþ transporting, lysosomal 70 kDa, V1 subunit A Argininosuccinate synthetase (ASS), transcript variant 2 Interleukin 15, transcript variant 1 B-cell CLL/lymphoma 6 (zinc finger protein 51), transcript variant 2 Tissue-type heart Ellis-van Creveld syndrome protein (EVC) mRNA, complete cds [AF216184] Interleukin 2 receptor, beta EGF-containing fibulin-like extracellular matrix protein 1, transcript variant 1 Thyrotropin-releasing hormone Major histocompatibility complex, class II, DO beta ATPase, Hþ transporting V0 subunit e2 Cysteine and glycine-rich protein 2 Olfactomedin 4 Solute carrier family 15 (Hþ/peptide transporter), member 2 Calbindin 2, 29 kDa (calretinin), transcript variant CALB2 Secreted frizzled-related protein 4 Catenin (cadherin-associated protein), alpha 2 Nuclear receptor subfamily 4, group A, member 2, transcript variant 1 Dual oxidase 1, transcript variant 1 kinesin family member 20A Proenkephalin Periostin, osteoblast specific factor Low density lipoprotein receptor-related protein 4 Solute carrier family 16 (monocarboxylic acid transporters), member 6 G protein-coupled receptor 64 RAN binding protein 17 Endothelin 3, transcript variant 3 Chromosome 10 open reading frame 3 Centromere protein E, 312 kDa KIAA0888 protein Collagen, type XVI, alpha 1

Fold change

No. of probes

3.37 3.33 3.32

4 2 3

3.31 3.28 3.27 3.26 3.22 3.22

4 5 1 5 2 3

3.20 3.20 3.18 3.17 3.16 3.15 3.14 3.14 3.14 3.13 3.12 3.09 3.09 3.09 3.08 3.05 3.04 3.04 3.03 3.03 3.02 3.02

1 1 1 1 3 3 2 2 2 3 1 2 2 4 3 2 1 3 4 1 2 2

3.01 3.00 21.69 11.06 9.82 9.62 9.35 8.44 8.40 8.33 8.02 7.05 6.61 6.33 6.16 6.04 5.87 5.61 5.52 5.50 5.30 5.24 5.20 5.17 4.89

3 2 2 5 2 2 2 2 1 1 3 3 2 1 3 2 2 3 4 2 4 1 2 5 2


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TABLE 1 Continued.

Gene name

Fold change

No. of probes

UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 12 (GalNAc-T12) Ankyrin 3, node of Ranvier (ankyrin G), transcript variant 1 Calpain 6 (CAPN6) Hydroxyprostaglandin dehydrogenase 15-(NAD) Solute carrier family 7 (cationic amino acid transporter, yþ system), member 1 Matrix metallopeptidase 26 Leucine-rich repeat containing 17, transcript variant 2 Potassium voltage-gated channel, subfamily G, member 1, transcript variant 1 Cytochrome P450, family 2, subfamily J, polypeptide 2 Microfibrillar-associated protein 2, transcript variant 1 Alkaline phosphatase, liver/bone/kidney CDC20 cell division cycle 20 homologue (S. cerevisiae) Gremlin 2 homologue, cysteine knot superfamily (Xenopus laevis) SRY (sex determining region Y)-box 17 Transforming, acidic coiled-coil containing protein 3 Hairy/enhancer-of-split related with YRPW motif 2 Progestin and adipoQ receptor family member IV Hypothetical protein MGC11242 Hydroxysteroid (11-beta) dehydrogenase 2 Kinesin family member 11 Neuregulin 2, transcript variant 5 Olfactomedin 1, transcript variant 3 Cordon-bleu homologue (mouse) Topoisomerase (DNA) II alpha 170 kDa Kinetochore associated 2 KIAA0802 protein Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 5 Discs, large homologue 7 (Drosophila) Asp (abnormal spindle)-like, microcephaly associated (Drosophila) SAM pointed domain-containing ets transcription factor Kynurenine 3-monooxygenase (kynurenine 3-hydroxylase) cAMP responsive element-binding protein 3-like 1 ATPase, Naþ/Kþ transporting, beta 1 polypeptide Peroxisomal D3,D2-enoyl-CoA isomerase, transcript variant 2 Isocitrate dehydrogenase 1 (NADPþ), soluble Carbonyl reductase 3 Chromosome 11 open reading frame 8 Creatine kinase, brain A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 8 Baculoviral IAP repeat-containing 3 (BIRC3), transcript variant 1 Deafness, autosomal recessive 31 KH domain-containing, RNA-binding, signal transduction associated 3 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 4 (GalNAc-T4) Transmembrane, prostate androgen-induced RNA, transcript variant 1 Kinesin family member 4A Potassium inwardly rectifying channel, subfamily J, member 2 BRCA1-associated RING domain 1 Mitogen-activated protein kinase kinase 6, transcript variant 1 Oral-facial-digital syndrome 1 Phospholipase A1 member A RAD54 homologue B (S. cerevisiae), transcript variant 1 PDZ-binding kinase NDRG family member 2, transcript variant 1 Extracellular matrix protein 1, transcript variant 2 Protein regulator of cytokinesis 1 (PRC1), transcript variant 1 Msh homeo box homologue 1 (Drosophila)

4.85

3

4.79 4.76 4.72 4.72 4.66 4.64 4.63 4.54 4.48 4.44 4.39 4.30 4.24 4.08 4.07 4.06 4.03 4.03 4.01 4.00 3.99 3.99 3.98 3.88 3.85 3.84 3.84 3.79 3.78 3.78 3.77 3.73 3.71 3.68 3.66 3.65 3.61 3.59

6 2 3 2 1 1 5 1 2 4 3 5 3 1 4 4 1 1 2 5 4 2 1 3 3 2 1 4 1 3 2 4 1 3 3 1 3 2

3.58 3.54 3.51 3.50

2 3 2 4

3.50 3.50 3.47 3.47 3.45 3.44 3.42 3.42 3.42 3.40 3.34 3.29 3.26

3 1 2 2 2 3 2 3 2 2 3 1 3

Gene symbol GALNT12c ANK3 CAPN6b HPGD SLC7A1 MMP26c LRRC17c KCNG1c CYP2J2 MFAP2c ALPLc CDC20c GREM2c SOX17c TACC3c HEY2c PAQR4c MGC11242c HSD11B2 KIF11c NRG2c OLFM1c COBL TOP2Ac KNTC2c KIAA0802c SERPINA5c DLG7c ASPMc SPDEFc KMOc CREB3L1 ATP1B1c PECIc IDH1 CBR3 C11orf8c CKB ADAMTS8 BIRC3 DFNB31 KHDRBS3 GALNT4c TMEPAIc KIF4Ac KCNJ2 BARD1c MAP2K6b OFD1 PLA1Ac RAD54B PBKc NDRG2b,c ECM1c PRC1c MSX1c


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TABLE 1 Continued.

Gene symbol CCNB2c LRRC1 SORDb,c EPHB3c TMSL8c RASSF2c TTC21B OPRK1 TMEM16Ac CRABP2c FLJ10719c PRKCQc CDC2c BUB1Bc STEAP4 HEY1

Gene name Cyclin B2 Leucine-rich repeat containing 1 Sorbitol dehydrogenase EPH receptor B3 Thymosin-like 8 Ras association (RalGDS/AF-6) domain family 2, transcript variant 1 mRNA for KIAA1992 protein [AB082523] Opioid receptor, kappa 1 Transmembrane protein 16A Cellular retinoic acid-binding protein 2 Hypothetical protein FLJ10719 Protein kinase C, theta Cell division cycle 2, G1 to S and G2 to M, transcript variant 1 BUB1 budding uninhibited by benzimidazoles 1 homologue beta (yeast) STEAP family member 4 Hairy/enhancer-of-split related with YRPW motif 1

Fold change

No. of probes

3.23 3.23 3.21 3.20 3.20 3.19 3.17 3.17 3.13 3.10 3.10 3.08 3.06 3.05 3.04 3.03

3 3 5 2 2 1 2 4 4 3 1 1 2 2 2 3

a

Genes were validated genes by RT-PCR. Genes included as gold standard receptivity biomarkers (25). c Genes belonging to the endometrial receptivity transcriptomic signature. b


the disease emerge, especially tumor classification (26–28) and complex functions (29, 30) such as endometrial receptivity. The aim of this study is to develop a customized endometrial receptivity array (ERA) and to define the transcriptomic signature for human endometrial receptivity. To prove its translational efficiency, we designed a bioinformatic test with predictive power to classify the human endometrium gene expression profile that is compatible with LHþ7 and to detect the endometrial disorders relating to it.

MATERIALS AND METHODS The ERA Gene Selection To select the genes involved in human endometrial receptivity as candidates to be included in the ERA, we analyzed the different gene expression profile in the entire human genome between the receptive and the prereceptive endometrium (gene selection set) using the raw expression data from our previous work (31). We performed a t-test and the genes showing an absolute fold-change >3 and a false discovery rate