Site-specific gene expression profiles and novel molecular prognostic factors in patients with lower gastrointestinal adenocarcinoma diffusely metastatic to liver or peritoneum.
BACKGROUND
Generally, colorectal and high-grade appendiceal cancers are treated similarly; treatment approach is primarily based on tumor histology and stage of disease. Patients with adenocarcinoma of the lower gastrointestinal tract frequently experience diffuse metastases isolated to liver or peritoneum and have a poor survival. Identification of novel molecular pathways in metastases from these patients may identify novel targets and prognostic factors.


METHODS
Microarray analyses of 20 metastatic tumors from patients with colorectal adenocarcinoma isolated to liver or peritoneum and eight high-grade appendiceal adenocarcinoma metastatic to peritoneum were performed using oligonucleotide microarray.


RESULTS
In an unsupervised hierarchical cluster analysis of 2-fold upregulated or downregulated genes, there was a clear site-specific segregation of liver versus peritoneal metastases. Genes primarily involved in metastasis, angiogenesis, cell cycle regulation, cell proliferation, and cell adhesion were distinctly altered between these two metastatic sites. Among the metastasis genes, the average expression levels of LI-cadherin, ALCAM, CD2, and CD14 were significantly higher in both metastatic sites. TIMP1 was overexpressed in both sites where as TIMP-2, IGF-1, and HIF-1alpha were upregulated only in peritoneal metastases demonstrating the potential benefit of metastasis site-specific treatments. Subsets of genes significantly associated with poor survival were defined, a RET proto-oncogene interacting gene, GOLGA5, was highly predictive for survival in patients with colorectal adenocarcinoma.


CONCLUSIONS
These results demonstrate that liver and peritoneal metastases of lower GI adenocarcinoma have distinct gene expression patterns; these distinctions may help in the development of therapies based on site of metastases.
Varghese
Sheelu
S
Division of Surgical Oncology, Department of Surgery, University of Maryland School of Medicine and the Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore 21201, USA.
Burness
Monika
M
Xu
Hui
H
Beresnev
Tatiana
T
Pingpank
James
J
Alexander
H Richard
HR
D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000556:secondary; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger