Abstract
Despite significant advances have been achieved in the genetic characterization of sporadic colorectal cancer (sCRC), the precise genetic events leading to the development of distant metastasis remain poorly understood. Thus, accurate prediction of metastatic disease in newly-diagnosed sCRC patients remains a challenge. Here, we evaluated the specific genes and molecular pathways associated with the invasive potential of colorectal tumor cells, through the assessment of the gene expression profile (GEP) of coding and non-coding genes in metastatic (MTX) vs. non-metastatic (non-MTX) primary sCRC tumors followed for >5 years. Overall, MTX tumors showed up-regulation of genes associated with tumor progression and metastatic potential while non-MTX cases displayed GEP associated with higher cell proliferation, activation of DNA repair and anti-tumoral immune/inflammatory responses. Based on only 19 genes a specific GEP that classifies sCRC tumors into two MTX-like and non-MTX-like molecular subgroups was defined which shows an independent prognostic impact on patient overall survival, particularly when it is combined with the lymph node status at diagnosis. In summary, we show an association between the global GEP of primary sCRC cells and their metastatic potential and defined a GEP-based classifier that provides the basis for further prognostic stratification of sCRC patients who are at risk of distant metastases.
Highlights
Despite significant progress made in the last decades, sporadic colorectal cancer still remains one of the most frequent causes of cancer death in the Western world [1]
We show an association between the global gene expression profile (GEP) of primary sporadic colorectal cancer (sCRC) cells and their metastatic potential and defined a GEP-based classifier that provides the basis for further prognostic stratification of sCRC patients who are at risk of distant metastases
Tumor-associated genes which were most overexpressed in MTX vs. non-MTX primary tumors, included genes involved in cell adhesion, extracellular matrix (ECM) and/or tissue remodeling processes, and progression and migration of tumor cells
Summary
Despite significant progress made in the last decades, sporadic colorectal cancer (sCRC) still remains one of the most frequent causes of cancer death in the Western world [1]. Most sCRC deaths are caused by metastatic dissemination of primary tumors, mainly into the liver [2]. We and others have recently shown that specific genomic alterations found in metastatic sCRC –e.g. del(17p) and del(22q)- are shared by primary tumors and their paired liver metastatic samples [2, 4,5,6,7], while absent in non-metastatic sCRC [8, 9]; interestingly, such genomic alterations of sCRC were shown to be closely associated with unique gene expression profiles (GEP) [6, 7, 10]. Simultaneous assessment of the GEP of both mRNA and non-coding (nc)RNA, might further contribute to better understand the molecular pathways involved in sCRC, via more accurate definition of those GEP that are responsible for the metastatic potential of primary CRC tumor cells
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