Tumor associated chromosomal instability drives colorectal adenoma to adenocarcinoma progression based on 17 year follow up evidence

Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally. Adenomas, precursors to CRC, can be diagnosed early, but the genetic events leading to adenoma-adenocarcinoma conversion remain unclear. This study explored the role of chromosomal instabilities (CINs) in this conversion. Over a 17-year follow-up period, 119 adenomas were analyzed using low-coverage whole-genome sequencing (LC-WGS) and Ultrasensitive Chromosomal Aneuploidy Detector. Risk factors for adenocarcinoma development were identified through logistic regression analysis, and survival was assessed using Kaplan-Meier curves. CIN was found in 32% of adenomas, with a higher incidence in high-grade adenomas (P = 0.0359). Common chromosomal changes included loss of 18q, 1p, and 17p and gain of 8q (MYC), 20q, and 7p (EGFR). During the 17-year follow-up, 88 patients experienced recurrence, including 40 cases of adenomas and 48 cases of progression to adenocarcinoma. CIN was identified in 40% of progression cases, 33.6% of adenoma recurrence cases, and 26% of nonrecurrent cases. A strong genetic linkage was observed before and after tumor transformation, with a high match between the tumors and matched prior adenomas. CIN was significantly associated with disease progression (HR: 2.5, 95% CI: 1.4-4.5, P = 0.00162) and was an independent risk factor. Additionally, MFN2 gene copy number deletion was linked to recurrence and/or progression after resection, with reduced expression in tumor tissues. In conclusion, CIN is a key risk factor for adenoma recurrence and progression, and MFN2 gene copy number deletion is associated with adverse outcomes, providing insights for more accurate clinical prognostication of adenoma-to-adenocarcinoma transformation.