Abstract 717: Pan-cancer analysis of <i>TRIM37</i> copy-number and development of fit-for-screening in situ hybridization tools
Authors: 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
Journal: Cancer Research (2025)

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.