Dataset Information

The Genomic Heterogeneity of FIGO Grade 3 Endometrioid Carcinoma Impacts Diagnostic Accuracy and Reproducibility.

ABSTRACT: The Cancer Genome Atlas (TCGA) identified 4 groups of endometrial carcinomas based on an integrated genomic characterization: POLE ultramutated (POLE), microsatellite instability-high, copy number-low (CN-L), and copy number-high (CN-H). In that study, CN-H comprised all of the serous carcinoma cases and 25% of all International Federation of Gynecology and Obstetrics (FIGO) Grade 3 endometrioid carcinoma cases. In this study, 2 expert gynecologic pathologists undertook a morphologic reassessment of the FIGO Grade 3 endometrioid carcinoma subset of the TCGA study cohort, including an analysis for evidence of serous differentiation. Interobserver variability ?values are reported for the histologic evaluation of all 4 genomic clusters, and diagnostic discrepancies are discussed. Overall, there were 55 agreements, 6 disagreements, and 14 deferrals. Of the 75 cases analyzed, 6 cases had a consensus morphologic diagnosis of serous carcinoma, but only 2 of these cases had a serous carcinoma genotype, whereas the remaining 4 cases were genotypically endometrioid carcinoma. For the CN-H group, 2 of 15 cases were serous carcinoma by morphology and genotype, whereas at least 1 pathologist interpreted the remaining 13 cases as endometrioid carcinoma. The interobserver agreement rate was highest in the CN-L group (90%; ?=0.9), compared with the other genomic groups (POLE: 62%, ?=0.55; microsatellite instability-high: 78%, ?=0.74; and CN-H: 53%, ?=0.48). Our review confirms that most high-grade endometrial carcinomas diagnosed by TCGA as FIGO Grade 3 endometrioid carcinoma are indeed endometrioid carcinomas by morphology and genotype, and that the reproducibility of histologic diagnosis between pathologists varies between the TCGA-integrated genomic clusters.

SUBMITTER: Hussein YR

PROVIDER: S-EPMC4934379 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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The Genomic Heterogeneity of FIGO Grade 3 Endometrioid Carcinoma Impacts Diagnostic Accuracy and Reproducibility.

Hussein Yaser R YR Broaddus Russell R Weigelt Britta B Levine Douglas A DA Soslow Robert A RA

International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 20160101 1

The Cancer Genome Atlas (TCGA) identified 4 groups of endometrial carcinomas based on an integrated genomic characterization: POLE ultramutated (POLE), microsatellite instability-high, copy number-low (CN-L), and copy number-high (CN-H). In that study, CN-H comprised all of the serous carcinoma cases and 25% of all International Federation of Gynecology and Obstetrics (FIGO) Grade 3 endometrioid carcinoma cases. In this study, 2 expert gynecologic pathologists undertook a morphologic reassessmen ...[more]

PMID: 26166718

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Project description:Diffuse intrinsic pontine glioma (DIPG) and midline high-grade glioma (mHGG) are lethal childhood brain tumors. Spatial genomic heterogeneity has been well-described in adult HGG but has not been comprehensively characterized in pediatric HGG. We performed whole exome sequencing on 38-matched primary, contiguous, and metastatic tumor sites from eight children with DIPG (n?=?7) or mHGG (n?=?1) collected using a unique MRI-guided autopsy protocol. Validation was performed using Sanger sequencing, Droplet Digital polymerase-chain reaction, immunohistochemistry, and fluorescent in-situ hybridization.Median age at diagnosis was 6.1 years (range: 2.9-23.3 years). Median overall survival was 13.2 months (range: 11.2-32.2 months). Contiguous tumor infiltration and distant metastases were observed in seven and six patients, respectively, including leptomeningeal dissemination in three DIPGs. Histopathological heterogeneity was evident in seven patients, including intra-pontine heterogeneity in two DIPGs, ranging from World Health Organization grade II to IV astrocytoma. We found conservation of heterozygous K27M mutations in H3F3A (n?=?4) or HIST1H3B (n?=?3) across all primary, contiguous, and metastatic tumor sites in all DIPGs. ACVR1 (n?=?2), PIK3CA (n?=?2), FGFR1 (n?=?2), and MET (n?=?1) were also intra-tumorally conserved. ACVR1 was co-mutated with HIST1H3B (n?=?2). In contrast, PDGFRA amplification and mutation were spatially heterogeneous, as were mutations in BCOR (n?=?1), ATRX (n?=?2), and MYC (n?=?1). TP53 aberrations (n?=?3 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved.Spatial conservation of prognostically-relevant and therapeutically-targetable somatic mutations in DIPG and mHGG contrasts the significant heterogeneity of driver mutations seen in adult HGG and supports uniform implementation of diagnostic biopsy in DIPG and mHGG to classify molecular risk groups and guide therapeutic strategy.

Dataset Information

The Genomic Heterogeneity of FIGO Grade 3 Endometrioid Carcinoma Impacts Diagnostic Accuracy and Reproducibility.

Publications

The Genomic Heterogeneity of FIGO Grade 3 Endometrioid Carcinoma Impacts Diagnostic Accuracy and Reproducibility.

Similar Datasets

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