Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer.

Abstract

Simple SummaryAbout 10% of colorectal cancer patients presents with oligo-metastatic disease. The aim of our study was to assess genetic and immunologic dynamics underlying the oligo-metastatic status, evaluating genotype-phenotype correlations in a clean and homogeneous clinical model of liver-limited metastatic colorectal cancer. We show that loss of KRAS and SMAD4 mutations characterizes the oligo-metastatic disease while a progressive mutational evolution (gain in KRAS, PI3KCA, BRAF and SMAD4) is observed in poly-metastatic evolving disease. Furthermore, high granzyme-B+ T-cells infiltration is found in oligo-metastatic lesions. This study can support innovative strategies to monitor clinical evolution and to induce regressive genetic trajectories in cancer.Genetic dynamics underlying cancer progression are largely unknown and several genes involved in highly prevalent illnesses (e.g., hypertension, obesity, and diabetes) strongly concur to cancer phenotype heterogeneity. To study genotype-phenotype relationships contributing to the mutational evolution of colorectal cancer (CRC) with a focus on liver metastases, we performed genome profiling on tumor tissues of CRC patients with liver metastatic disease and no co-morbidities. We studied 523 cancer-related genes and tumor-immune microenvironment characteristics in primary and matched metastatic tissues. We observed a loss of KRAS and SMAD4 alterations and a high granzyme-B+ T-cell infiltration when the disease did not progress. Conversely, gain in KRAS, PIK3CA and SMAD4 alterations and scarce granzyme-B+ T-cells infiltration were observed when the tumor evolved towards a poly-metastatic spread. These findings provide novel insights into the identification of tumor oligo-metastatic status, indicating that some genes are on a boundary line between these two clinical settings (oligo- vs. poly-metastatic CRC). We speculate that the identification of these genes and modification of their evolution could be a new approach for anti-cancer therapeutic strategies.