Clonal Evolution in Paired Endometrial Intraepithelial Neoplasia/Atypical Hyperplasia and Endometrioid Adenocarcinoma

Publication date: Available online 14 July 2017
Source:Human Pathology
Author(s): Mariano Russo, James Broach, Kathryn Sheldon, Kenneth R. Houser, Dajiang J. Liu, Joshua Kesterson, Rebecca Phaeton, Carrie Hossler, Nadine Hempel, Maria Baker, Jordan M. Newell, Richard Zaino, Joshua I. Warrick
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 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>0.1). 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 TCGA (The Cancer Genome Atlas) subtype, with three classified as "copy number low endometrioid" and three classified as "microsatellite instability hypermutated." While paired EIN/AH and carcinoma samples were clonal, private mutations (i.e. 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.



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