Abstract 717: Pan-cancer analysis of <i>TRIM37</i> copy-number and development of fit-for-screening in situ hybridization tools

Abstract Background: Elevated TRIM37 protein levels, often driven by genomic copy number (CN) gains in cancer cells, lead to loss of the pericentriolar material during mitosis and increased dependence on PLK4-mediated centriole assembly. This synthetic lethal hypothesis is being tested in a phase I clinical trial evaluating the activity of the PLK4 inhibitor, RP-1664, in advanced solid tumors with TRIM37 CN gains or overexpression (LIONS, NCT06232408). In support of this clinical study, we characterized TRIM37 CN and RNA expression across a large genomic database and by imaging-based DNA and RNA in-situ hybridization. Methods: Whole exomes and transcriptomes from &amp;gt;12,000 adult solid tumors were analyzed for TRIM37 CN gain (CN &amp;gt; ploidy) or amplification (amp, CN ≥ ploidy + 2), respectively, or TRIM37 RNA expression (BostonGeneTM). Locus specific probes for fluorescence in-situ hybridization (FISH) were developed for TRIM37 and centromere 17 (CEP17). TRIM37 RNA-ISH was developed using the RNAscopeTM system (ACD BioTM). Results: Across adult solid tumors, TRIM37 amps, were most frequent in breast (9%), lung adenocarcinoma (5%), and melanoma (5%). Using the lower cutoff inclusive of TRIM37 gains, CN events were most often observed in urinary tract cancer (33%), lung adenocarcinoma (32.2%), breast cancer (26%), and squamous cell lung carcinoma (24.2%). TRIM37 CN levels were correlated with TRIM37 RNA expression in all indications examined. TRIM37 CN level was inversely correlated with segment length (coef -1.76, p-value = 6.1e-20). ERBB2 (HER2) is located approximately 19 megabases (mb) from TRIM37 and was often co-amplified, with 73% of ERBB2 gain/amps also having TRIM37 gain/amps. TRIM37 focal amps (&amp;lt;5.6 mb) were enriched in samples with co-occurring ERBB2 focal amps, even though these events were on different segments. HER2-enriched breast cancer had the highest percentage of focal TRIM37 amps (56%) and high-level amps (≥ 5 copies; 60%). To identify TRIM37 high patients clinically, we developed RNA and DNA ISH assays. TRIM37 DNA FISH ratio and ploidy corrected CN by NGS were strongly correlated (N=16, Pearson correlation = 0.89, p-value = 3.4x10-6). DNA FISH ratio was positively associated with RNA-ISH scores (Jonckheere-Terpstra test, P = 0.03), and of 16 TRIM37 FISH positive DNA-FISH samples, 14 were scored 2-3+ (≥4 copies/cell), while 2, scored 1+ (1-3 copies per cell) by RNA-ISH. Conclusions: A considerable population of adult solid tumors are TRIM37-high. Creation of fit-for-screening tools employing in-situ hybridization techniques may provide enhanced sensitivity for identification of patients with TRIM37-high tumors. Citation Format: Isabel Soria-Bretones,Joseph D. Schonhoft,Esha Jain,Nikita Kotlov,Parham Nejad,Daria F. Goncharova,Oleg A. Baranov,Jessica K. Scher,Elizabeth A. Sheehan,Vladimir A. Kushnarev,Konstantin Chernyshov,Gary Marshall,Ian M. Silverman,Victoria Rimkunas. Pan-cancer analysis of TRIM37 copy-number and development of fit-for-screening in situ hybridization tools [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 717.