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

SIMPLE SUMMARY: About 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. ABSTRACT: 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.