Comprehensive genomic analysis contrasting primary colorectal cancer and matched liver metastases

Abstract

Recent studies have revealed that colorectal cancer (CRC) displays intratumor genetic heterogeneity, and that the cancer microenvironment plays an important role in the proliferation, invasion and metastasis of CRC. The present study performed genomic analysis on paired primary CRC and synchronous colorectal liver metastasis (CRLM) tissues collected from 22 patients using whole-exome sequencing, cancer gene panels and microarray gene expression profiling. In addition, immunohistochemical analysis was used to confirm the protein expression levels of genes identified as highly expressed in CRLM by DNA microarray analysis. The present study identified 10 genes that were highly expressed in CRLM compared with in CRC, from 36,022 probes obtained from primary CRC, CRLM and normal liver tissues by gene expression analysis with DNA microarrays. Of the 10 genes identified, five were classified as encoding 'matricellular proteins' [(osteopontin, periostin, thrombospondin-2, matrix Gla protein (MGP) and glycoprotein nonmetastatic melanoma protein B (GPNMB)] and were selected for immunohistochemical analysis. Osteopontin was strongly expressed in CRLM (6 of 22 cases: 27.3%), but not in CRC (0 of 22: 0%; P=0.02). Periostin also exhibited strong immunoreactivity in CRLM (17 of 22: 68.2%) compared with in CRC (7 of 22: 31.8%; P=0.006). Thrombospondin-2 exhibited strong immunoreactivity in both CRC and CRLM (54.5% in CRC, 45.5% in CRLM; P=0.55). GPNMB and MGP were rarely positive for both CRC and CRLM. A comparison of immunoreactive positive factors for these five genes revealed the complexities of gene expression in CRLM. Of the cases examined, 16 (72.7%) cases of CRC showed zero or only one positive immunoreactive factor. By contrast, CRLM showed more frequent and multiple immunoreactive factors; for example, 16 cases (72.7%) shared two or more factors, which was statistically more frequent than in CRC (P=0.007). The present study revealed the genomic heterogeneity between paired primary CRC and CRLM, in terms of cancer cell microenvironment. This finding may lead to novel diagnostic and therapeutic targets in the era of genome-guided personalized cancer treatment.

TROP2 Represents a Negative Prognostic Factor in Colorectal Adenocarcinoma and Its Expression Is Associated with Features of Epithelial–Mesenchymal Transition and Invasiveness

“…These genes encode the extracellular matrix proteins LAMA3 and LAMC2 , which have been detected in invasive colon cancer cells and are regulated by transforming growth factor beta 1 and the hepatocyte growth factor produced in the tumor microenvironment [ 97 ]. Another EMT marker/promoter, Spp1 , is highly expressed in liver metastases [ 98 ] and promotes tumor cell migration and invasion [ 99 ]; PLAUR is responsible for the binding and conversion of plasminogen to active plasmin and the subsequent degradation of the extracellular matrix, which in turn promotes invasion and metastasis [ 100 ]. Finally, matrilysin is a matrix metallopeptidase that can degrade extracellular matrix components such as laminins, fibronectin, collagens, and proteoglycans and promote tumor cell invasion and metastatic spread [ 101 ].…”

Targeting Metastatic Colorectal Cancer with Immune Oncological Therapies

“…They concluded that in the metastatic setting, molecular features of the primary tumour were less prognostic and that analysis of the metastatic deposit differed and could more powerfully predict clinical outcomes based on three groups: canonical, immune and stromal subtypes. Differential genomic signatures between the primary tumour and the metastatic deposit have been demonstrated by other groups [ 29 ].…”

TROP2 represents a negative prognostic factor in colorectal adenocarcinoma and its expression is associated with features of epithelial-mesenchymal transition and invasiveness

“…These genes encode the extracellular matrix proteins LAMA3 and LAMC2 , which have been detected in invasive colon cancer cells and are regulated by transforming growth factor beta 1 and hepatocyte growth factor produced in the tumor microenvironment [97]. Another EMT marker/promoter, Spp1 , is highly expressed in liver metastases [98] and promotes tumor cell migration and invasion [99]; PLAUR is responsible for the binding and conversion of plasminogen to active plasmin and subsequent degradation of the extracellular matrix, which in turn promotes invasion and metastasis [100]. Finally, matrilysin is a matrix metallopeptidase that can degrade extracellular matrix components such as laminins, fibronectin, collagens, and proteoglycans and promote tumor cell invasion and metastatic spread [101].…”