Methylation analysis reveals epigenetic congruence between bone sarcomas with H3-3A mutations and malignant giant cell tumors of bone Journal Article
| Authors: | Saoud, C.; Benhamida, J.; Borsu, L.; Villafania, L.; Linos, K.; Brannon, A. R.; Sinchun, H.; Morris, C.; Vaynrub, M.; Bartelstein, M.; Healey, J.; Tap, W.; Bale, T. A.; Nacev, B. A.; Ladanyi, M.; Hameed, M. R. |
| Article Title: | Methylation analysis reveals epigenetic congruence between bone sarcomas with H3-3A mutations and malignant giant cell tumors of bone |
| Abstract: | Hotspot mutations in H3-3A gene are key drivers in giant cell tumor of bone (GCTB). Rare primary bone sarcomas also harbor this mutation, but their clinicopathologic characteristics and molecular profiles, as well as their relationship to conventional and malignant GCTB (MGCTB) and high-grade conventional osteosarcoma (HGOS), are largely undefined. Herein, we present a series of 10 H3-3A mutated bone sarcomas (BSH3-3A) with a comparative clinicopathologic, mutational, and epigenetic analysis with conventional GCTB, MGCTB, and HGOS. BSH3-3A comprised of 6 high-grade osteosarcomas, 4 undifferentiated pleomorphic sarcoma of bone and occurred in 7 women and 3 men with a mean age of 46 years (28-74 years). The tumors involved femur (n = 4), talus (n = 2), spine (n = 2), pelvis (n = 1), and 1 unknown site. Epiphysis involvement was noted in 2 femoral tumors. In majority of the cases, BSH3-3A showed cellular proliferation of epithelioid and/or spindle cells, hyperchromatic nuclei, and conspicuous pleomorphism with or without osteoid production. One case exhibited both low- and high-grade osteosarcoma components. The mutational profile of BSH3-3A was different than that of conventional HGOS with significantly less frequent TP53 mutations. The genomic index, which reflects the degree of genomic complexity, was also significantly lower in BSH3-3A compared with HGOS, yet higher than GCTB. DNA methylation analysis revealed that most BSH3-3A and MGCTB cases form a distinct cluster, positioned near but separate from GCTB, and clearly separated from HGOS. Differential methylation analysis revealed that BSH3-3A exhibited the highest degree of similarity to MGCTB in comparison to HGOS and GCTB. Survival analysis showed that outcomes for BSH3-3A do not differ significantly from those observed in HGOS or MGCTB. Finally, BSH3-3A tumors, although radiologically and histologically identical to high-grade bone sarcomas lacking H3-3A mutations, display epigenetic features similar to MGCTB and have a significantly less complex genomic profile than HGOS, despite comparable clinical outcomes. © 2025 United States & Canadian Academy of Pathology |
| Keywords: | osteosarcoma; adult; cancer survival; clinical article; controlled study; human tissue; aged; middle aged; survival analysis; gene mutation; clinical feature; histopathology; cisplatin; doxorubicin; gemcitabine; adjuvant therapy; comparative study; methotrexate; pelvis; cancer grading; cell proliferation; ipilimumab; cyclophosphamide; vincristine; dna methylation; docetaxel; oncogene; epigenetics; pazopanib; spindle cell; femur; epiphysis; bone sarcoma; giant cell tumor of bone; clinical outcome; nivolumab; osteoclastoma; human; male; female; article; conventional osteosarcoma; talus; undifferentiated pleomorphic sarcoma of bone; genetic profile; epithelioid histiocyte; h3-3a; malignant giant cell tumor of bone; h3 3a gene; osteoblastic osteosarcoma |
| Journal Title: | Modern Pathology |
| Volume: | 38 |
| Issue: | 7 |
| ISSN: | 0893-3952 |
| Publisher: | Nature Research |
| Date Published: | 2025-07-01 |
| Start Page: | 100763 |
| Language: | English |
| DOI: | 10.1016/j.modpat.2025.100763 |
| PUBMED: | 40157506 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | PDF mixes up MSK author: Sinchun Hwang first & last name -- The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Meera R. Hameed -- Source: Scopus |
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