Abstract P1-01-15: Clinical relevance of TRIM37 gene expression in breast cancer

Abstract Background: Tripartite motif-containing protein 37 (TRIM37) is an oncogenic histone H2A ubiquitin ligase that is overexpressed in a subset of breast cancers. TRIM37 was suggested to be associated with chemotherapy resistance and metastasis of triple-negative breast cancer (TNBC) in in vivo and in vitro studies. Breast cancer with TRIM37 amplification is sensitive to polo-like kinase 4 (PLK4) inhibition. On the other hand, clinical relevance of TRIM37 in breast cancer was never investigated. Material and Methods: Total of 6836 breast cancer patients from three large patient cohorts (Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), GSE96058, GSE25066 and GSE20194. Gene set enrichment analysis (GSEA) was performed. The high and low expression of TRIM37 gene were divided by median. Results: TRIM37 expression was significantly associated with worse survival (disease-free (DFS), disease-specific (DSS), and overall survival (OS)) in ER-positive/HER2-negative breast cancer (p=0.012, p=0.011, and p=0.003, respectively), but not in the other subtypes. TRIM37 expression was higher in HER2-positive among the subtypes. TRIM37 expression correlated with Nottingham histological grade (p<0.001), and with MKI-67 expression (p<0.001) consistently in METABRIC and GSE96058 cohorts. TRIM37 high expression enriched cell proliferation-related gene sets; E2F targets, G2M checkpoints, mitotic spindle, and MYC targets v1 and v2, as well as DNA repair gene sets regardless of subtypes. TRIM37 high expression was also associated with RAD51C and/or PLK4 expression, which are DNA repair related genes. In agreement, silent and non-silent mutation rate and altered fraction were all significantly elevated in TRIM37 high tumors regardless of subtypes. TRIM37 expression correlated with response to Cisplatin, Paclitaxel, and Tamoxifen in breast cancer cell line study (r=0.655, r=0.446, and r=0.9, respectively). TRIM37 high tumors demonstrated significantly worse pathological complete response after neoadjuvant chemotherapy in ER-positive/HER2-negative patients (p=0.002), but the opposite in TNBC (p=0.025) in GSE25066 cohort, but this result was not validated by GSE20194, a cohort with very small samples size. Interestingly, TRIM37 low expression enriched immune related gene sets; inflammatory response, IL2 signaling, IL6 signaling, TNF-a signaling, and allograft rejection in ER-positive/HER2-negative patients, but not in TNBC. Indeed, CD8 central memory T cells and CD4 effector memory T cells are highly infiltrated in TRIM37 low tumors consistently in both METABRIC and GSE96058 in ER-positive/HER2-negative patients, but not in TNBC. Taken together, TRIM37 high expression was associated with cell proliferation regardless of subtypes, but TRIM37 low expression was associated with high tumor infiltrating lymphocytes and immune response that may have contributed to the survival difference in ER-positive/HER2-negative patients, but not in TNBC. Conclusions: In conclusion, TRIM37 expression is associated with cell proliferation and DNA repair, less tumor infiltrating lymphocytes and immune response, and with worse survival in ER-positive/HER2-negative breast cancer. Citation Format: Junko Tsuchida, Rongrong Wu, Maiko Endo, Kazuki Moro, Chie Toshikawa, Yu Koyama, Hiroshi Ichikawa, Takaaki Hanyu, Yamato Takabe, Kazuyasu Takizawa, Yoshifumi Shimada, Takashi Kobayashi, Takashi Ishikawa, Jun Sakata, Toshifumi Wakai, Kazuaki Takabe. Clinical relevance of TRIM37 gene expression in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-01-15.