Mullerian adenosarcoma: Clinicopathologic and molecular characterization highlighting recurrent BAP1 loss and distinctive features of high-grade tumors Journal Article
| Authors: | Momeni Boroujeni, A.; Kertowidjojo, E.; Wu, X.; Soslow, R. A.; Chiang, S.; Da Silva, E. M.; Weigelt, B.; Chui, M. H. |
| Article Title: | Mullerian adenosarcoma: Clinicopathologic and molecular characterization highlighting recurrent BAP1 loss and distinctive features of high-grade tumors |
| Abstract: | Mullerian adenosarcoma is an uncommon mesenchymal tumor of the gynecologic tract. Most cases are low-grade, while high-grade adenosarcomas are rare and not well studied. Herein, we characterize the clinicopathologic and molecular features of 27 adenosarcomas of gynecologic origin, enriched for high-grade tumors subjected to targeted panel sequencing. Sarcomatous overgrowth was more frequently seen in high-grade compared to low-grade tumors (12/17, 71%, vs 1/10, 10%, p = 0.004) and heterologous elements were exclusive to high-grade cases (n = 7, p = 0.03). All deaths were from high-grade disease (advanced primary, n = 2, or recurrence, n = 5). Genetic alterations specific to high-grade adenosarcomas have known associations with chromosome instability, including TP53 mutations (n = 4) and amplifications of MDM2 (n = 2) and CCNE1 (n = 2). Somatic ATRX frameshift mutations were found in 2 patients with high-grade recurrences following a primary low-grade adenosarcoma and ATRX deletion in 1 high-grade adenosarcoma with an adjacent low-grade component. The fraction of genome altered by copy number alterations was significantly higher in high-grade compared to low-grade adenosarcomas (P = 0.001). Other recurrent genetic alterations across the entire cohort included BAP1 homozygous deletions (n = 4), DICER1 mutations (n = 4), ARID1A mutations (n = 3), TERT promoter mutations (n = 2) and amplification (n = 1), as well as alterations involving members of the PI3K and MAPK signaling pathways. One tumor harbored an ESR1-NCOA3 fusion and another had an MLH1 homozygous deletion. Immunohistochemical analysis for BAP1 revealed loss of nuclear expression in 6/24 (25%) cases, including all four tumors with BAP1 deletions. Notably, out of 196 mesenchymal neoplasms of gynecologic origin, BAP1 homozygous deletion was only found in adenosarcomas (P = 0.0003). This study demonstrates that high-grade adenosarcomas are heterogeneous at the molecular level and are characterized by genomic instability and TP53 mutations; ATRX loss may be involved in high-grade transformation of low-grade adenosarcoma; and BAP1 inactivation appears to be a specific pathogenic driver in a subset of adenosarcomas. © 2022, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology. |
| Keywords: | immunohistochemistry; adult; clinical article; controlled study; human tissue; protein expression; aged; middle aged; primary tumor; young adult; unclassified drug; gene sequence; promoter region; frameshift mutation; gene deletion; genetics; sequence deletion; clinical feature; cancer recurrence; advanced cancer; cancer grading; gene; gene amplification; protein depletion; protein; cohort analysis; genetic association; pathology; phosphatidylinositol 3 kinase; cancer mortality; dead box protein; dead-box rna helicases; homozygosity; genomic instability; tumor suppressor proteins; fusion gene; homozygote; gene loss; cell nucleus; tumor suppressor protein; uterus cancer; uterine neoplasms; mlh1 gene; ribonuclease iii; ubiquitin thiolesterase; female genital tract cancer; phosphatidylinositol 3-kinases; dicer1 protein, human; adenosarcoma; mapk signaling; bap1 protein; arid1a gene; atrx gene; mullerian adenosarcoma; humans; human; female; article; dicer1 gene; tumor mutational burden; bap1 protein, human |
| Journal Title: | Modern Pathology |
| Volume: | 35 |
| Issue: | 11 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2022-11-01 |
| Start Page: | 1684 |
| End Page: | 1694 |
| Language: | English |
| DOI: | 10.1038/s41379-022-01160-1 |
| PUBMED: | 36138078 |
| PROVIDER: | scopus |
| PMCID: | PMC10319431 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
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