Comprehensive genomic analysis contrasting primary colorectal cancer and matched liver metastases: a retrospective study

Abstract

(Background)Recent studies have revealed that colorectal cancer (CRC) displays intratumor genetic heterogeneity, and the cancer microenvironment play an important role in the proliferation, invasion, and metastasis of CRC.(Methods)We performed genomic analysis on 22 paired patients with primary CRC and synchronous colorectal liver metastasis (CRLM) using whole-exome sequencing, cancer gene panels, and microarray gene expression profiling. In addition, immunohistochemical analysis was used to confirm the protein expression of genes identified as highly expressed in CRLM by DNA microarray analysis.(Results)A total of 22 paired patients were enrolled in this study, including 13 (59.1%) colon and 9 (40.9%) rectal cancer patients. All patients had synchronous liver metastasis and did not have any other extrahepatic metastases. We identified 11 probes (10 genes) that were highly expressed in CRLM compared to CRC, from 36022 probes obtained from primary CRC, CRLM, and normal liver tissues, using gene expression analysis with DNA microarray. Of the 11 probes (10 genes), 5 genes classified as encoding “matricellular proteins” (osteopontin, periostin, thrombospondin-2, MGP, and GPNMB) 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 showed strong immunoreactivity in CRLM (17 of 22: 68.2%) compared to 7 of 22 (31.8%) in CRC (p=0.006). Thrombospondin-2 showed strong immunoreactivity both in 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 5 genes revealed the complexities of gene expression in CRLM. Of the cases, 16 (72.7%) CRC revealed zero or only one positive immunoreactivity. On the other hand, CRLM revealed more frequent multiple immunoreactivity; 16 cases (72.7%) shared 2 or more factors, which was statistically more frequent in CRLM than in CRC (p=0.007).(Conclusions)This study revealed the genomic heterogeneity between paired primary CRC and CRLM in terms of cancer cell microenvironment. This finding will lead to new diagnostic and therapeutic targets in the era of genome-guided personalized cancer treatment.(Trial registration)This study was retrospectively registered.