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

2020 ◽  
Author(s):  
Akio Shiomi ◽  
Masatoshi Kusuhara ◽  
Takashi Sugino ◽  
Teiichi Sugiura ◽  
Keiichi Ohshima ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Dna Microarray ◽  
Genomic Analysis ◽  
Immunohistochemical Analysis ◽  
Normal Liver ◽  
Matricellular Proteins ◽  
Microarray Gene Expression ◽  
Strong Immunoreactivity

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.

scholarly journals Prospective validation in epithelial tumors of a gene expression predictor of liver metastasis derived from uveal melanoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Petros Tsantoulis ◽  
Mauro Delorenzi ◽  
Ivan Bièche ◽  
Sophie Vacher ◽  
Pascale Mariani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Uveal Melanoma ◽  
Meta Analysis ◽  
Prognostic Score ◽  
Penalized Regression ◽  
Breast Cancer Patients ◽  
Public Data

AbstractPredicting the risk of liver metastasis can have important prognostic and therapeutic implications, given the availability of liver-directed therapy. Uveal melanoma has a striking predisposition for liver metastasis despite the absence of anatomical proximity. Understanding its biology may uncover factors promoting liver metastasis in other malignancies. We quantified gene expression by RNAseq in 76 uveal melanomas and combined with public data in a meta-analysis of 196 patients. The meta-analysis of uveal melanoma gene expression identified 63 genes which remained prognostic after adjustment for chromosome 3 status. Two genes, PTP4A3 and JPH1, were selected by L1-penalized regression and combined in a prognostic score. The score predicted liver-specific relapse in a public pan-cancer dataset and in two public colorectal cancer datasets. The score varied between colorectal consensus molecular subtypes (CMS), as did the risk of liver relapse, which was lowest in CMS1. Additional prospective validation was done by real-time PCR in 463 breast cancer patients. The score was significantly correlated with liver relapse in hormone receptor positive tumors. In conclusion, the expression of PTP4A3 and JPH1 correlates with risk of liver metastasis in colorectal cancer and breast cancer. The underlying biological mechanism is an interesting area for further research.

Prognostic signatures of oligometastasis in colorectal cancer liver metastasis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3588-3588
Author(s):  
Sajid A. Khan ◽  
Philip Paty ◽  
Zhaoshi Zeng ◽  
Jun Lu
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Gene Family ◽  
Messenger Rna ◽  
Molecular Subtype ◽  
Prognostic Information ◽  
Hoxa Cluster ◽  
Hox Gene ◽  
Colorectal Cancer Liver Metastasis

3588 Background: Knowledge of molecular differences between limited metastasis (oligometastasis) and widespread metastases may provide biomarkers for selection of patients who will benefit from curative metastasis resection and provide useful prognostic information. In this study, we detect messenger RNA expressional patterns in patients with colorectal cancer liver metastasis (CRCLM) and identify networks of coding and noncoding RNAs corresponding to oligometastatic phenotype. Methods: RNA was prepared from frozen tumor tissue of 55 patients with CRCLM patients treated with liver resection and/or biopsy of their metastatic tumors with greater than 15 years of follow-up. Survival was calculated and stratified according to risk of recurrence. Cases were subject to RNA-Sequencing experiments with paired end sequencing. Results: RNA analysis with TopHat and Cuffdiff found significant differences in transcript expression according to recurrence for 667 genes (P < 0.05). Of these transcripts, 166 had a greater than 2-fold gene expression between groups when comparing mean Fragments Per Kilobase of transcript per Million mapped reads (FPKM) (P < 0.05). Unsupervised hierarchical clustering revealed distinct genomic patterns based on clinical outcome. A supervised gene expression analysis revealed a differential expression of genes in the Homeobox ( HOX) family (P < 0.05). Overexpression of individual members of the HOX gene family are associated with prognosis. Upregulation of the HOXD11 gene was associated with cure in 60% of cases while downregulation was associated with 5-year overall survivals of 16% (P = 0.023). Furthermore, when clusters of HOX family members were compared, we found that expression correlated with survival, underlining the importance of this gene family in oligometastasis biology. A high ratio of the HOXD cluster to HOXA cluster was associated with a long recurrence free survival (P = 0.002). Conclusions: Common genomic signatures characterize patients with liver oligometastasis from primary colorectal cancer. The HOX gene family strongly correlates with prognosis and represents a unique molecular subtype of patients. Further mechanistic studies of the HOX gene family in metastases are underway.

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