Abstract 1567: Honing in on the metastasis machinery

Abstract

Abstract A prevailing 'principal' in oncology posits that metastases is the last step in a strict sequence of tumorigenic events. However, despite decades of widespread breast & colon cancer (CA) screening and interceptive surgeries, there hasn't been any decrease in metastatic (M) stages, a discrepancy that undermines the validity of this principle. Others suggested unlinking tumorigenesis from metastasis, supporting an evolutionarily convergent model. We reasoned that cells' ability to circulate (physiologic in white blood cells) is mediated by putative gene(s)-encoded metastatic apparatus (MA), hence subject to alteration during the genomic turmoil of tumorigenesis. It follows that essential components of MA cannot be chromosomally deleted in M CAs; stage I CA may indicate deactivated MA. The overarching goal here is to identify genes encoding the putative MA. Chromosomal deletions are relevant since they are definitive, testable and inform mutational and epigenetic events. Of note, the retained gene list (RGL) in any CA includes cell-viability genes (CVG). Methods: The Cancer Genome Atlas (TCGA) is a well-curated, clinically annotated public database. We examined copy number variation to determine the RGL1 in stage 1 cancers (CVG); and RGL2 in metastatic CAs. To account for possible heterogeneity or redundancy in MA in different CA types, we performed the RGL2 analysis within organ systems. By TCGA's criteria, deletion was defined as a microarray expression of ←0.3. Regions of interest, therefore, were RGL2 excluding RGL1. Results: Table lists RGL2 excluding RGL1 per CA site Conclusion: We present a plausible mechanistic approach to identify RGL encoding the putative MA for interrogation by gene-editing experiments. Our data suggest plurality of the MA given zero overlap for the entire set. Performing the analysis in additional cases within embryonal ontogeny or by driver oncogene might be useful in this pursuit. This work has implications for screening, diagnostic, prognostic surgical/adjuvant CA therapy, and novel antineoplastics. RGL2 (excluding RGL-1 2,405 regions): unique genes that are never deleted in any of the listed metastatic cases in TCGA per site (n) and the number of overlapping genes for further testing consideration Gastrointestinal Exocrine Gastrointestinal Mucosa Lung Genitourinary Breast Head & Neck Thyroid Pancreas 392 (100) Esophagus (49) 1982 Adenocarcinoma (169) 2800 Bladder (216) 434 BC (191) 341 H&N (337) 275 Thyroid (224) 8292 Gastric (52) 7773 Squamous (90) 2101 Kidney (111) 10189 Number of Overlapping unique genes 392 825 368 87 341 275 8292 Pan-CA Overlap ZERO Citation Format: Jim Zhongning Chen, Tyler C. Fugere, Farah Mazahreh, Bradley Fugere, Eric Delgiacco, Ahmad Mazin M. Safar. Honing in on the metastasis machinery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1567.