Molecular Classification Of Endometrial Carcinoma Research Articles

Molecular testing in endometrial carcinoma - joint recommendation of Czech Oncological Society, Oncogynecological Section of the Czech Gynecological and Obstetrical Society, Society of Radiation Oncology, Biology and Physics, and the Society of Czech Pathologists.

Molecular classification of endometrial carcinoma is becoming an important part of the dia-gnostic process with direct therapeutic implications. Recent international guidelines, including the joint recommendation of the European Society of Gynaecological Oncology, the European Society for Radiotherapy and Oncology and the European Society of Pathology include the molecular classification into standard dia-gnostic algorithms. Molecular testing of endometrial carcinomas is also recommended in the latest (5th edition) of the World Health Organization classification of female genital tumors. Due to the need to implement these recommendations in practice, representatives of four professional societies of the Czech Medical Association of J. E. Purkyně (the Czech Oncological Society, the Oncogynecological Section of the Czech Gynecological and Obstetrical Society, the Society of Radiation Oncology, Biology and Physics, and the Society of Czech Pathologists) organized a meeting focused on this topic. Recommendation for molecular testing of endometrial carcinoma in routine dia-gnostic practice in the Czech Republic.

Molecular testing in endometrial carcinoma – joint recommendation of Czech Oncological Society, Oncogynecological Section of the Czech Gynecological and Obstetrical Society, Society of Radiation Oncology, Biology and Physics, and the Society of Czech Pathologists

Molecular classification of endometrial carcinoma is becoming an important part of the diagnostic process with direct therapeutic implications. Recent international guidelines, including the joint ESGO-ESTRO-ESP recommendation, include the molecular classification into standard diagnostic algorithms. Molecular testing of endometrial carcinomas is also recommended in the latest (5th) edition of the WHO classification of Female Genital Tumors. Due to the need to implement these recommendations in practice, representatives of four professional societies of Czech Medical Association of J. E. Purkyně (Czech Oncological Society, Oncogynecological Section of the Czech Gynecological and Obstetrical Society, Society of Radiation Oncology, Biology and Physics, and the Society of Czech Pathologists) organized a meeting focused on this topic. The result of this meeting is a joint recommendation for molecular testing of endometrial carcinoma in routine diagnostic practice in the Czech Republic.

Impact of Molecular Classification on Treatment Paradigms in Uterine Cancers.

This article will discuss the recent data on the prognostic significance of molecular classification of endometrial carcinoma, as well as its impact on directing treatment decisions. Molecular classification has emerged as a complement to the current paradigm of endometrial cancer (EC) risk stratification. POLE mutations appear to portend favorable prognoses, but data are insufficient to indicate withholding treatment based on this signature. Copy number high (CNH) EC carries a worse prognosis and may benefit from more aggressive therapy. MMRd tumors are likely to have other prognostic features that indicate adjuvant treatment and many recurrences respond favorably to pembrolizumab. Progression of molecular profiling may allow further discrimination of the no specific molecular profile (NSMP) group. Treatment for this group remains largely based on conventional risk factors. For both the NSMP and the CNH groups, treatment with lenvatinib and pembrolizumab is an attractive contemporary option for recurrence management. Molecular classification is a useful adjunct to conventional risk stratification paradigms for both prognostic counseling and treatment selection. Clinical trials incorporating molecular signatures in assigning treatment strategies may further elucidate the value of this classification system.

Molecular subtype diagnosis of endometrial carcinoma: comparison of the next-generation sequencing panel and Proactive Molecular Risk Classifier for Endometrial Cancer classifier

The Cancer Genome Atlas-based molecular classification of endometrial carcinoma (EC) has the potential to better identify those patients whose disease is likely to behave differently than predicted when using traditional risk stratification; however, the optimal approach to molecular subtype assignment in routine practice remains undetermined. The aim of this study was to compare the results of two different widely available approaches to diagnosis the EC molecular subtype. EC specimens from 60 patients were molecularly subclassified using two different methods, by using the FoundationOne CDx next-generation sequencing (NGS) panel and using the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) classifier and performing immunostainingfor mismatch repair proteins and p53. POLE mutation status was derived from FoundationOne results in both settings. Molecular classification based on ProMisE was successful for all 60 tumors. Microsatellite instability status could be determined based on the NGS panel results in 53 of 60 tumors, so ProMisE and NGS molecular subtype assignment could be directly compared for these 53 tumors. Molecular subtype diagnosis based on NGS and ProMisE was in agreement for 52 of 53 tumors. One tumor was microsatellite stable but showed loss of MLH1 and PMS2 expression. Molecular subtype diagnosis of EC based on the NGS panel of formalin-fixed paraffin-embedded ECs and based primarily on immunostaining (ProMisE) yields identical results in 98.1% (52/53, kappa = 0.97) of cases. Although results obtained using these two approaches are comparable, each has advantages and disadvantages that will influence the choice of the method to be used in clinical practice.

ARID1A and CTNNB1/β-Catenin Molecular Status Affects the Clinicopathologic Features and Prognosis of Endometrial Carcinoma: Implications for an Improved Surrogate Molecular Classification.

Simple SummaryTranslation of the molecular characterization of endometrial cancer into the clinical practice is emerging as a challenge. This study investigates the feasibility and the prognostic impact of the novel surrogate TCGA molecular classification of endometrial carcinoma into the clinical setting proposing an immuno-molecular algorithm supplemented with ARID1A and CTNNB1/β-catenin analysis. The integrated clinicopathologic and molecular approach developed in this study could represent a workable and useful method in routine clinical practice for improving risk stratification and patient management.The collaborative Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups of endometrial carcinoma (EC) based on molecular alterations: (i) the ultramutated subtype that encompasses POLE mutated (POLE) cases; (ii) the hypermutated subtype, characterized by MisMatch Repair deficiency (MMRd); (iii) the copy-number high subtype, with p53 abnormal/mutated features (p53abn); (iv) the copy-number low subtype, known as No Specific Molecular Profile (NSMP). Although the prognostic value of TCGA molecular classification, NSMP carcinomas present a wide variability in molecular alterations and biological aggressiveness. This study aims to investigate the impact of ARID1A and CTNNB1/β-catenin alterations by targeted Next-generation sequencing (NGS) and immunohistochemistry (IHC) in a consecutive series of 125 molecularly classified ECs. NGS and IHC were used to assign surrogate TCGA groups and to identify molecular alterations of multiple target genes including POLE, PTEN, ARID1A, CTNNB1, TP53. Associations with clinicopathologic parameters, molecular subtypes, and outcomes identified NSMP category as the most heterogeneous group in terms of clinicopathologic features and outcome. Integration of surrogate TCGA molecular classification with ARID1A and β-catenin analysis showed NSMP cases with ARID1A mutation characterized by the worst outcome with early recurrence, while NSMP tumors with ARID1A wild-type and β-catenin alteration had indolent clinicopathologic features and no recurrence. This study indicates how the identification of ARID1A and β-catenin alterations in EC represents a simple and effective way to characterize NSMP tumor aggressiveness and metastatic potential.

Molecular classification of endometrial carcinoma across Canada: Variation in practice and opportunities to move towards consistency of care

Objective: The Cancer Genome Atlas (TCGA)-inspired molecular classification of endometrial carcinoma enables consistent classification of tumors, provides prognostic and predictive information for patients and clinicians, identifies women who may have inherited cancer syndromes, and enables stratification of clinical trials to study treatment efficacy within biologically like tumors. Herein we characterize the molecular subtype distribution, management, and outcomes of recently diagnosed (2016) endometrial carcinomas managed across Canada and assess conventional management compared to how molecular classification may be implemented in direct care, reducing over-treatment in women whose endometrial carcinoma may be cured by surgery alone and avoiding under-treatment, with implications for both patient outcomes and health resources.

Molecular Subgroups of Endometrial Carcinoma in Romanian Patients

Molecular classification of endometrial carcinoma (EC) has represented a breakthrough ever since the TCGA (The Cancer Genome Atlas) project published it in 2013. Four distinct molecular subgroups were recognized based on somatic copy number alterations and tumor mutational burden: POLE (polymerase-epsilon) ultramutated, MSI (microsatellite instability) hypermutated (MSI-H), copy number low (CNL) and copy number high (CNH). However, implementing a standardized algorithm in current practice is far from being definitive. Our purpose in this study was to determine different molecular subgroups in a cohort of Romanian patients using cost effective and available immuno-histochemistry markers and outline statistical associations with different parameters. Tissue microarrays encompassing 50 cases with previously diagnosed ECs were tested for ER, PR, HER2, p53, MSH6 and PMS2 and results showed 68% MSI-H cases with statistical correlation with tumor size ] 2 cm (p=0.028) and no association with overall survival. CNH ECs were reported in 26% of cases and showed important statistical significance with TILs (p=0.041) and no correlations with overall survival. The CNL subgroup was reported in 74% of ECs cases and showed statistical significance with the histopathological subtype (p=0.006), pT (removal of primary tumor according to AJCC/UICC convention) (p=0.033), risk category according to ESMO (European Society of Medical Oncology) criteria (p=0.022) and ER expression (p=0.002). Five-year overall survival was 84%. Molecular classification is an important additional tool in current pathology guidelines for reporting ECs, but it is not currently standardized or available in all laboratories. Its importance in evolving treatment strategies for this disease is well documented so we strongly recommend routine testing for molecular prognostic factors.

Interpretation of somatic POLE mutations in endometrial carcinoma.

Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours (‘POLE‐ultramutated’) within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency, and the results from six in silico tools on 82 ECs with whole‐exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution > 20%, T>G substitutions > 4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100 mut/Mb. A scoring system to assess these alterations (POLE‐score) was developed; based on their scores, 7/18 (39%) additional tumours with EDM were classified as POLE‐ultramutated ECs, and the six POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non‐EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI‐H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co‐existent with MSI‐H showed genomic alterations characteristic of POLE‐ultramutated ECs. In a pooled analysis of 3361 ECs, 13 ECs with DNA mismatch repair deficiency (MMRd)/MSI‐H and a pathogenic POLE EDM had a 5‐year recurrence‐free survival (RFS) of 92.3%, comparable to previously reported POLE‐ultramutated ECs. Additionally, 14 cases with non‐pathogenic POLE EDM and MMRd/MSI‐H had a 5‐year RFS of 76.2%, similar to MMRd/MSI‐H, POLE wild‐type ECs, suggesting that these should be categorised as MMRd, rather than POLE‐ultramutated ECs for prognostication. This work provides guidance on classification of ECs with POLE mutations, facilitating implementation of POLE testing in routine clinical care. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Interlaboratory Concordance of ProMisE Molecular Classification of Endometrial Carcinoma Based on Endometrial Biopsy Specimens.

Molecular classifiers improve the consistency of categorization of endometrial carcinoma and provide valuable prognostic information. We aimed to evaluate the interlaboratory agreement in ProMisE assignment across 3 dedicated Canadian gynecologic oncology centers. Fifty cases of endometrial carcinoma diagnosed on biopsy were collected from 3 centers and 3 unstained sections were provided to each participating site so that immunohistochemistry for MSH6, PMS2, and p53 could be performed and interpreted at each center, blinded to the original diagnoses and the results from other centers. A core was taken for DNA extraction and POLE mutation testing. Overall accuracy and κ statistic were assessed. MSH6, PMS2, and p53 could be assessed for all 50 cases, with agreement for 140/150 results. There was a high level of agreement in molecular classification (κ=0.82), overall. Cases with a discordant result for one of the features used in classification (n=10) were reviewed independently and the most common reason for disagreement was attributable to the weak p53 staining in 1 laboratory (n=4). Interpretive error in PMS2 (n=1) and MSH6 (n=2) assessment accounted for 3 of the remaining disagreements. Interpretive error in the assessment of p53 was identified in 2 cases, with very faint p53 nuclear reactivity being misinterpreted as wild-type staining. These results show strong interlaboratory agreement and the potential for greater agreement if technical and interpretive factors are addressed. Several solutions could improve concordance: central quality control to ensure technical consistency in immunohistochemical staining, education to decrease interpretation errors, and the use of secondary molecular testing.

Classification of Endometrial Carcinoma: New Perspectives Beyond Morphology.

Endometrial carcinoma has been traditionally divided into type 1 or endometrioid type that is usually moderate to well differentiated and type 2 that is usually poorly differentiated with high histologic grade and aggressive clinical behavior. However, interobserver diagnostic agreement is suboptimal, particularly among the high-grade histotypes. Furthermore, recent data indicate that this histotype assignment does not independently correlate with survival. In recent years, there has been remarkable progress in our understanding of the molecular basis of endometrial carcinoma and extensive molecular studies have been performed under The Cancer Genome Atlas Program (TCGA) leading to molecular classification of endometrial carcinoma that has been shown to be significantly prognostic. This classification system divides the tumors into 4 subgroups namely, polymerase ε exonuclease (POLE) ultramutated, hypermutated microsatellite instability, copy number low, and copy number high (serous-like). Carcinomas with POLE domain hotspot mutations are highly prognostically favorable; those with copy number alterations and TP53 mutations are highly aggressive; and microsatellite unstable and "copy number low" endometrioid are associated with intermediate prognoses. The TCGA applied methods that are too costly and cumbersome for widespread implementation into routine clinical practice. Several other groups have attempted to identify these categories by using immunohistochemical biomarkers rather than molecular studies. Immunohistochemical biomarkers have been used successfully to identify all the subgroups except for POLE ultramutated, which requires sequencing for proper categorization. It is hoped that future studies will identify a suitable biomarker for POLE mutation so that this classification can be routinely used in all medical centers.

Reclassifying endometrial carcinomas with a combined morphological and molecular approach.

Currently, endometrial carcinoma diagnosis is based on morphology, often supplemented by immunohistochemistry. However, especially with high-grade endometrial carcinomas, there is considerable interobserver variability in diagnosis calling into question the value of morphology in stratifying these tumours into different prognostic and therapeutic groups. The purpose of this review is to provide an update on the recently described molecular classification of endometrial carcinoma. In 2013, the Cancer Genome Atlas (TCGA) published a seminal molecular study of endometrial carcinomas of endometrioid, serous and mixed types. This revealed that endometrial carcinoma consists of four intrinsic molecular subtypes: POLE (ultramutated), microsatellite instabilty (hypermutated), copy-number low (also referred to as microsatellite stable or no specific molecular profile) and copy-number high (serous-like). These four molecular subtypes are of prognostic significance with POLE tumours having the best and copy-number high, the worst prognosis. It is likely that TCGA classification will become the mainstay of endometrial carcinoma diagnosis in the coming years and various strategies (Proactive Molecular Risk Classifier for Endometrial Cancer and the TransPORTEC classifiers) have been proposed for a combined morphological-molecular classification which can be undertaken in most pathology laboratories. This will necessitate routine undertaking of POLE mutation analysis in some endometrial carcinomas and require an appropriate infrastructure.

Molecular classification of endometrial carcinoma applied to endometrial biopsy specimens: Towards early personalized patient management

BackgroundThe current risk stratification systems used to guide management of endometrial cancer are based on irreproducible post surgical pathological information, hence the need for more reliable classification systems. Using microarray and sequencing technologies, TCGA recently identified four prognostically significant endometrial carcinoma subtypes, which subsequently proved reproducible using clinically applicable surrogate tests. Using these tests, we sought to determine the level of concordance between endometrial biopsies and subsequent hysterectomy specimens in assessing the molecular classification of endometrial carcinoma. Materials and methodsFifty biopsies with corresponding hysterectomy specimens for endometrial carcinomas were collected. Additionally, 10 cases of biopsy proven atypical hyperplasia/EIN who were found to have endometrial carcinoma on resection were included. IHC for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2 and MSH6) and P53 was performed. Microsatellite instability analysis was performed by PCR and Sanger sequencing was performed to detect mutations in exons 9 and 13 of the POLE gene. The level of concordance for tumor grade, histologic subtype, immunohistochemical and molecular profile in both specimens was determined using Cohen's kappa estimates. ResultsA high level of concordance was achieved for MMR-loss, MSI-high, P53-wild and abnormal types. In contrast, grade and histologic subtype showed only moderate levels of agreement. POLE gene mutation was detected in two patients. For both cases, mutations were detected only in resection specimens. When comparing atypical hyperplasia/EIN with subsequent hysterectomy tumor, the profile was identical to that of endometrial carcinoma. ConclusionIn our cohort of endometrial carcinoma, a high level of concordance was achieved between biopsy and hysterectomy specimens for MMR-loss, MSI-high, P53-wild and abnormal types, superior to that of grade and histologic subtype, providing earlier and more reliable prognostic information to inform management. Similar concordance could not be achieved for POLE mutation, given the low frequency of this mutation in our study.

Towards early personalized patient management: Molecular classification of endometrial carcinoma applied to endometrial biopsy specimens

Towards early personalized patient management: Molecular classification of endometrial carcinoma applied to endometrial biopsy specimens

Pathologic Prognostic Factors in Endometrial Carcinoma (Other Than Tumor Type and Grade).

Although endometrial carcinoma (EC) is generally considered to have a good prognosis, over 20% of women with EC die of their disease, with a projected increase in both incidence and mortality over the next few decades. The aim of accurate prognostication is to ensure that patients receive optimal treatment and are neither overtreated nor undertreated, thereby improving patient outcomes overall. Patients with EC can be categorized into prognostic risk groups based on clinicopathologic findings. Other than tumor type and grade, groupings and recommended management algorithms may take into account age, body mass index, stage, and presence of lymphovascular space invasion. The molecular classification of EC that has emerged from the Cancer Genome Atlas (TCGA) study provides additional, potentially superior, prognostic information to traditional histologic typing and grading. This classifier does not, however, replace clinicopathologic risk assessment based on parameters other than histotype and grade. It is envisaged that molecular and clinicopathologic prognostic grouping systems will work better together than either alone. Thus, while tumor typing and grading may be superseded by a classification based on underlying genomic abnormalities, accurate assessment of other pathologic parameters will continue to be key to patient management. These include those factors related to staging, such as depth of myometrial invasion, cervical, vaginal, serosal surface, adnexal and parametrial invasion, and those independent of stage such as lymphovascular space invasion. Other prognostic parameters will also be discussed. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.

Amplification of 1q32.1 Refines the Molecular Classification of Endometrial Carcinoma.

Purpose: Molecular classification of endometrial cancer identified distinct molecular subgroups. However, the largest subset of endometrial cancers remains poorly characterized and is referred to as the "nonspecific molecular profile" (NSMP) subgroup. Here, we aimed at refining the classification of this subgroup by profiling somatic copy-number aberrations (SCNAs).Experimental Design: SCNAs were analyzed in 141 endometrial cancers using whole-genome SNP arrays and pooled with 361 endometrial cancers from The Cancer Genome Atlas. Genomic Identification of Significant Targets in Cancer (GISTIC) identified statistically enriched SCNAs and penalized Cox regression assessed survival effects. The prognostic significance of relevant SCNAs was validated using multiplex ligation-dependent probe amplification in 840 endometrial cancers from the PORTEC-1/2 trials. Copy-number status of genes was correlated with gene expression to identify potential cancer drivers. One plausible oncogene was validated in vitro using antisense oligonucleotide-based strategy.Results: SCNAs affecting chromosome 1q32.1 significantly correlated with worse relapse-free survival (RFS) in the NSMP subgroup (HR, 2.12; 95% CI, 1.26-3.59; P = 0.005). This effect was replicated in NSMP endometrial cancers from PORTEC-1/2 (HR, 2.34; 95% CI, 1.17-4.70; P = 0.017). A new molecular classification including the 1q32.1 amplification improved risk prediction of recurrence. MDM4 gene expression strongly correlated with 1q32.1 amplification. Silencing MDM4 inhibited cell growth in cell lines carrying 1q32.1 amplification, but not in those without MDM4 amplification. Vice versa, increasing MDM4 expression in nonamplified cell lines stimulated cell proliferation.Conclusions: 1q32.1 amplification was identified as a prognostic marker for poorly characterized NSMP endometrial cancers, refining the molecular classification of this subgroup. We functionally validated MDM4 as a potential oncogenic driver in the 1q32.1 region. Clin Cancer Res; 23(23); 7232-41. ©2017 AACR.

Pathology of Endometrial Carcinoma.

On a clinicopathological and molecular level, two distinctive types of endometrial carcinoma, type I and type II, can be distinguished. Endometrioid carcinoma, the typical type I carcinoma, seems to develop through an estrogen-driven "adenoma carcinoma" pathway from atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN). It is associated with elevated serum estrogen and high body mass index and expresses estrogen and progesterone receptors. They are mostly low grade and show a favorable prognosis. A subset progresses into high-grade carcinoma which is accompanied by loss of receptor expression and accumulation of TP53 mutations and behaves poorly. Other frequently altered genes in type I carcinomas are K-Ras, PTEN, and ß-catenin. Another frequent feature of type I carcinomas is microsatellite instability mainly caused by methylation of the MLH1 promoter. In contrast, the typical type II carcinoma, serous carcinoma, is not estrogen related since it usually occurs in a small uterus with atrophic endometrium. It is often associated with a flat putative precursor lesion called serous endometrial intraepithelial carcinoma (SEIC). The molecular pathogenesis of serous carcinoma seems to be driven by TP53 mutations, which are present in SEIC. Other molecular changes in serous carcinoma detectable by immunohistochemistry involve cyclin E and p16. Since many of the aforementioned molecular changes can be demonstrated by immunohistochemistry, they are useful ancillary diagnostic tools and may further contribute to a future molecular classification of endometrial carcinoma as recently suggested based on The Cancer Genome Atlas (TCGA) data.

Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: Earlier prognostic information to guide treatment

ObjectiveCategorization and risk stratification of endometrial carcinomas is inadequate; histomorphologic assessment shows considerable interobserver variability, and risk of metastases and recurrence can only be derived after surgical staging. We have developed a Proactive Molecular Risk classification tool for Endometrial cancers (ProMisE) that identifies four distinct prognostic subgroups. Our objective was to assess whether molecular classification could be performed on diagnostic endometrial specimens obtained prior to surgical staging and its concordance with molecular classification performed on the subsequent hysterectomy specimen. MethodsSequencing of tumors for exonuclease domain mutations (EDMs) in POLE and immunohistochemistry for mismatch repair (MMR) proteins and p53 were applied to both pre- and post-staging archival specimens from 60 individuals to identify four molecular subgroups: MMR-D, POLE EDM, p53 wild type, p53 abn (abnormal). Three gynecologic subspecialty pathologists assigned histotype and grade to a subset of samples. Concordance of molecular and clinicopathologic subgroup assignments were determined, comparing biopsy/curetting to hysterectomy specimens. ResultsComplete molecular and pathologic categorization was achieved in 57 cases. Concordance metrics for pre- vs. post-staging endometrial samples categorized by ProMisE were highly favorable; average per ProMisE class sensitivity(0.9), specificity(0.96), PPV(0.9), NPV(0.96) and kappa statistic 0.86(95%CI, 0.72–0.93), indicating excellent agreement. We observed the highest level of concordance for ‘p53 abn’ tumors, the group associated with the worst prognosis. In contrast, grade and histotype assignment from original pathology reports pre- vs. post-staging showed only moderate levels of agreement (kappa=0.55 and 0.44 respectively); even with subspecialty pathology review only moderate levels of agreement were observed. ConclusionMolecular classification can be achieved on diagnostic endometrial samples and accurately predicts the molecular features in the final hysterectomy specimens, demonstrating concordance superior to grade and histotype. This biologically relevant information, available at initial diagnosis, has the potential to inform management (surgery, adjuvant therapy) from the earliest time point in cancer care.

Investigation of calcium transport and regulation system in human placenta

The Cancer Genome Atlas–based molecular classification of endometrial carcinoma (EC) has the potential to better identify those patients whose disease is likely to behave differently than predicted when using traditional risk stratification; however, the optimal approach to molecular subtype assignment in routine practice remains undetermined. The aim of this study was to compare the results of two different widely available approaches to diagnosis the EC molecular subtype. EC specimens from 60 patients were molecularly subclassified using two different methods, by using the FoundationOne CDx next-generation sequencing (NGS) panel and using the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) classifier and performing immunostaining for mismatch repair proteins and p53. POLE mutation status was derived from FoundationOne results in both settings. Molecular classification based on ProMisE was successful for all 60 tumors. Microsatellite instability status could be determined based on the NGS panel results in 53 of 60 tumors, so ProMisE and NGS molecular subtype assignment could be directly compared for these 53 tumors. Molecular subtype diagnosis based on NGS and ProMisE was in agreement for 52 of 53 tumors. One tumor was microsatellite stable but showed loss of MLH1 and PMS2 expression. Molecular subtype diagnosis of EC based on the NGS panel of formalin-fixed paraffin-embedded ECs and based primarily on immunostaining (ProMisE) yields identical results in 98.1% (52/53, kappa = 0.97) of cases. Although results obtained using these two approaches are comparable, each has advantages and disadvantages that will influence the choice of the method to be used in clinical practice.