Genetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic development

• DOI: 10.1038/s42003-022-03884-x
• Publication Date: 2022-09-09T16:20:28Z
• Authors: Daniel Sobral; Marta Martins; Shannon Kaplan; Mahdi Golkaram; Michael Salmans; Nafeesa Khan; Raakhee Vijayarag...; Sandra Casimiro; Afonso Fernandes; Paula Borralho; Cristina Ferreira; Rui Pinto; Catarina Abreu; Ana Lúcia Costa; Shile Zhang; Traci Pawlowski; Jim Godsey; André Mansinho; Daniela Macedo; Soraia Lobo-Martins; Pedro Filipe; Rui Esteves; João Coutinho; Paulo Matos Costa; Afonso Ramires; Fernando Aldeia; António Quintela; Alex So; Li Liu; Ana Rita Grosso; Luis Costa
• Keywords: Chromosome instability; Tumor progression; Primary tumor; Tumor initiation; Tumor Heterogeneity

Abstract Colorectal cancer (CRC) is a highly diverse disease, where different genomic instability pathways shape genetic clonal diversity and tumor microenvironment. Although intra-tumor heterogeneity has been characterized in primary tumors, its origin consequences CRC outcome not fully understood. Therefore, we assessed intra- inter-tumor of prospective cohort 136 samples. We demonstrate that forged by asynchronous forms molecular alterations, mutational chromosomal collectively boost microenvironment heterogeneity. were able to depict predictor signatures cancer-related genes can foresee levels across the consensus subtypes (CMS) location. Finally, show high are associated with lower metastatic potential, whereas late-emerging copy number variations favor metastasis development polyclonal seeding. This study provides an exhaustive portrait interplay between CMS subtypes, depicting events predictive value progression development.