Clonal evolution in paired endometrial intraepithelial neoplasia/atypical hyperplasia and endometrioid adenocarcinoma

Autor: Rebecca Phaeton, Joshua I. Warrick, Nadine Hempel, Jordan M. Newell, Maria J. Baker, James R. Broach, Joshua Kesterson, Dajiang J. Liu, Kenneth R. Houser, Richard J. Zaino, Mariano Russo, Kathryn Sheldon, Carrie Hossler
Rok vydání: 2017
Předmět:
0301 basic medicine
Pathology
medicine.medical_specialty
DNA Copy Number Variations
Biopsy
Gene Dosage
Biology
Hysterectomy
DNA Mismatch Repair
Somatic evolution in cancer
Atypical hyperplasia
Pathology and Forensic Medicine
Clonal Evolution
03 medical and health sciences
0302 clinical medicine
Germline mutation
Biomarkers
Tumor
medicine
Carcinoma
Humans
Genetic Predisposition to Disease
Atypical Endometrial Hyperplasia
Aged
Cell Proliferation
Aged
80 and over
Endometrial intraepithelial neoplasia
High-Throughput Nucleotide Sequencing
Microsatellite instability
Middle Aged
medicine.disease
Immunohistochemistry
Molecular biology
Endometrial Neoplasms
Endometrial hyperplasia
DNA Repair Enzymes
Phenotype
030104 developmental biology
030220 oncology & carcinogenesis
Endometrial Hyperplasia
Mutation
Disease Progression
Female
Microsatellite Instability
Carcinoma
Endometrioid
Carcinoma in Situ
Zdroj: Human Pathology. 67:69-77
ISSN: 0046-8177
Popis: Endometrial intraepithelial neoplasia (EIN) and atypical endometrial hyperplasia (AH) are histomorphologically defined precursors to endometrioid adenocarcinoma, which are unified as EIN/AH by the World Health Organization. EIN/AH harbors a constellation of molecular alterations similar to those found in endometrioid adenocarcinoma. However, the process of clonal evolution from EIN/AH to carcinoma is poorly characterized. To investigate, we performed next-generation sequencing, copy number alteration (CNA) analysis, and immunohistochemistry for mismatch repair protein expression on EIN/AH and endometrioid adenocarcinoma samples from 6 hysterectomy cases with spatially distinct EIN/AH and carcinoma. In evaluating all samples, EIN/AH and carcinoma did not differ in mutational burden, CNA burden, or specific genes mutated (all P>.1). All paired EIN/AH and carcinoma samples shared at least one identical somatic mutation, frequently in PI(3)K pathway members. Large CNAs (>10 genes in length) were identified in 83% of cases; paired EIN/AH and carcinoma samples shared at least one identical CNA in these cases. Mismatch repair protein expression matched in all paired EIN/AH and carcinoma samples. All paired EIN/AH and carcinoma samples had identical The Cancer Genome Atlas subtype, with 3 classified as "copy number low endometrioid" and 3 classified as "microsatellite instability hypermutated." Although paired EIN/AH and carcinoma samples were clonal, private mutations (ie, present in only one sample) were identified in EIN/AH and carcinoma in all cases, frequently in established cancer-driving genes. These findings indicate that EIN/AH gives rise to endometrioid adenocarcinoma by a complex process of subclone evolution, not a linear accumulation of molecular events.
Databáze: OpenAIRE
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