Abstract 3345: Application of cGAS-immunopositive micronuclei as an indicator of tumor aggressiveness in liposarcoma

Abstract Background: Recent molecular biological studies have revealed that chromosomal instability (CIN) promotes the malignant phenotype of tumors. CIN causes chromosomal segregation errors, leading to micronuclei (MN) formation. Ruptured MNs activate the cGAS-STING pathway, an intracellular DNA sensor, and induce metastasis and invasion. Histological confirmation of MNs is thought to be uncertain and not reproducible. On the other hand, cGAS is localized in a subset of MN by immunohistochemistry, so we attempted to apply cGAS-positive MN as an indicator of CIN and tumor aggressiveness in liposarcoma, which is reported as one of the tumors with the highest frequency of CIN among various malignant tumors. Study Design: Formalin-fixed paraffin-embedded biopsy and surgical specimens of liposarcoma of four histological types, namely well-differentiated (WLPS) (n=18), dedifferentiated (DLPS) (n=32), myxoid (MLPS) (n=6), and pleomorphic liposarcoma (PLPS) (n=7) were examined. In addition, benign lipomatous tumors (n=17) were also tested. Ten cases of non-lipomatous high-grade sarcoma were used as controls. Because DLPS results from the dedifferentiation of WLPS, it comprises differentiated (W) and dedifferentiated (D) components. Immunohistochemical staining for cGAS was performed, and the number of cGAS-positive micronuclei in 500 tumor cells of each tumor was counted. For DLPS, dedifferentiated cells (D cells) in the D component and lipogenic cells (L cells) and non-lipogenic cells (N cells) in the W component were evaluated separately. Results: cGAS immunostain highlighted a subset of micronuclei, as well as mitotic figures, and some small punctate structures within the main nuclei. The average number of cGAS-positive MNs was 1.2 for benign lipomatous tumor (n=17), 1.0 for myxoid liposarcoma (MLPS, n=6), 34.1 for pleomorphic liposarcoma (PLPS, n=7), 23.2 for D cells in (DLPS, n=32), 3.1 for L cells and 3.6 for N cells in WLPS / W-component (n=43), 24.2 for referenced sarcomas, respectively. The number of cGAS-positive micronuclei was significantly higher in aggressive sarcomas (PLPS and D components of DLPS) than in translocation-associated sarcoma (MLPS), WLPS / W-component, and benign tumors. Although the D-component and W-component / WLPS share a similar complex karyotype, the number of c-GAS positive MNs was significantly higher in D cells rather than L cells (t-test, p=0.0001) and N cells (t-test, p=0.0002). Conclusion: MNs can be visualized by cGAS immunostain. Significant increases in cGAS-positive MNs were observed in aggressive liposarcomas with complex karyotypes. Furthermore, increased cGAS-positive MNs are associated with malignant progression in DLPS. cGAS-positive MNs may be applicable as an objective indicator of tumor aggressiveness and CIN. Citation Format: Kiyota Kato, Toru Motoi, Yu Naito, Masumi Ogawa, Chihiro Onda, Hideo Arai, Shin-ichiro Horiguchi, Toshihide Hirai, Tsunekazu Hishima. Application of cGAS-immunopositive micronuclei as an indicator of tumor aggressiveness in liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3345.