Article ; Online: High-Grade Endometrial Stromal Sarcomas With YWHAE::NUTM2 Gene Fusion Exhibit Recurrent CDKN2A Alterations and Absence of p16 Staining is a Poor Prognostic Marker.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
2023 Volume 36, Issue 3, Page(s) 100044
Abstract: High-grade endometrial stromal sarcomas (HGESSs) are aggressive uterine tumors harboring oncogenic fusion proteins. We performed a molecular study of 36 HGESSs with YWHAE::NUTM2 gene fusion, assessing co-occurring genetic events, and showed that these ... ...
| Abstract | High-grade endometrial stromal sarcomas (HGESSs) are aggressive uterine tumors harboring oncogenic fusion proteins. We performed a molecular study of 36 HGESSs with YWHAE::NUTM2 gene fusion, assessing co-occurring genetic events, and showed that these tumors frequently harbor recurrent events involving the CDKN2A locus on chromosome 9p. Using array-based copy number profiling and CDKN2A fluorescence in situ hybridization, we identified homozygous and hemizygous deletions of CDKN2A in 18% and 14% of tumors (n = 22 analyzed), respectively. While all YWHAE-rearranged HGESSs with retained disomy for CDKN2A were immunohistochemically positive for p16INK4 (p16), all tumors with homozygous deletion of CDKN2A showed complete absence of p16 staining. Of the 2 tumors with a hemizygous deletion of CDKN2A, 1 showed diffuse and strong p16 positivity, whereas the other showed complete absence of staining. In the p16-negative case, we did not find intragenic mutations or DNA promoter methylation to explain the p16 protein loss, implicating other mechanisms in the regulation of protein expression. In our cohort, subclonal or complete absence of p16 staining was associated with worse overall survival compared with positive p16 staining (1-year overall survival: 28.6% vs 90.7%, respectively; n = 32; P < .001), with all 7 patients in the p16-negative group having succumbed to their disease within 2 years of diagnosis. Our results suggested CDKN2A alterations as a cooperative driver of tumorigenesis in a subset of HGESSs with the YWHAE::NUTM2 gene fusion and showed p16 to be a potential prognostic marker. |
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| MeSH term(s) | Female ; Humans ; Endometrial Neoplasms/pathology ; Prognosis ; In Situ Hybridization, Fluorescence ; Sarcoma, Endometrial Stromal/genetics ; Sarcoma, Endometrial Stromal/pathology ; Homozygote ; Sequence Deletion ; Sarcoma/genetics ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Gene Fusion ; 14-3-3 Proteins/genetics ; 14-3-3 Proteins/metabolism | |||||
| Chemical Substances | Cyclin-Dependent Kinase Inhibitor p16 ; YWHAE protein, human ; 14-3-3 Proteins ; CDKN2A protein, human | |||||
| Language | English | |||||
| Publishing date | 2023-01-10 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 645073-8 | |||||
| ISSN | 1530-0285 ; 0893-3952 | |||||
| ISSN (online) | 1530-0285 | |||||
| ISSN | 0893-3952 | |||||
| DOI | 10.1016/j.modpat.2022.100044 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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