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A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients.

ABSTRACT: BACKGROUND: The newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the association between MACC1 tagging single nucleotide polymorphisms (SNPs) and overall survival in a large cohort of colorectal cancer patients. METHODS: The study included 318 subjects with histopathologically proven colorectal cancer at the Academic Teaching Hospital Feldkirch, Austria. Survival data were provided by the federal agency for statistics in Austria. Genomic DNA was isolated from formalin-fixed paraffin-embedded specimens; six tagging SNPs (rs1990172, rs3114446, rs10275612, rs3095007, rs3095009, and rs7780032), capturing most of the common variants of the MACC1 locus, were genotyped by SNaPshot assays. RESULTS: Over a mean follow up period of 5.3 (± 1.0) years, 94 deaths were recorded. Carriers of the G-allele of SNP rs1990172 showed a significantly decreased overall survival (additive HR = 1.38 [1.05-1.82]; p = 0.023). Multivariate analysis adjusted for age and UICC tumor stage confirmed this result (HR = 1.49 [1.12-1.98]; p = 0.007). Other investigated genetic variants of the MACC1 gene were not significantly associated with overall survival (p-values > 0.05). CONCLUSIONS: For the first time, our study investigated the influence of MACC1 tagging polymorphisms on overall survival suggesting SNP rs1990172 as a predictor for reduced overall survival in colorectal cancer patients. Further studies will be required to validate our findings.

SUBMITTER: Lang AH

PROVIDER: S-EPMC3282635 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients.

Lang Alois H AH Geller-Rhomberg Simone S Winder Thomas T Stark Nicole N Gasser Klaus K Hartmann Bernd B Kohler Bertram B Grizelj Ina I Drexel Heinz H Muendlein Axel A

BMC cancer 20120117

<h4>Background</h4>The newly discovered metastasis-associated in colon cancer-1 (MACC1) gene is a key regulator of the HGF/MET pathway. Deregulation of HGF/MET signaling is reported as a prognostic marker for tumorigenesis, early stage invasion, and metastasis. High expression levels of MACC1 have been associated with colon cancer metastasis and reduced survival. Potential links between the genetic diversity of the MACC1 locus and overall survival are unknown. We therefore investigated the assoc ...[more]

PMID: 22251819

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Project description:Metastasis-associsated in colon cancer 1 (MACC1), a newly identified oncogene, promotes tumor cell proliferation and invasion. In the present study, the expression of MACC1, hepatocyte growth factor (HGF) and its receptor, MET proto-oncogene (c-Met), was investigated in human gastric cancer tissues and adjacent normal tissues by immunohistochemistry. The association between the expression levels of the proteins and the clinicopathological parameters of the tumors were statistically analyzed. Furthermore, lentiviral particles expressing MACC1 were used to infect the hepatic satellite cell (HSC) line LX2. The expression of ?-smooth muscle actin (SMA), HGF, matrix metallopeptidase (MMP)-2 and MMP-9 in human HSCs was examined by western blotting and reverse transcription-quantitative polymerase chain reaction. Transwell assays were used to measure the effect of MACC1-infected or non-infected HSCs on the migration and invasion abilities of MKN45 and MKN74 gastric carcinoma cells in vitro. The results demonstrated that positive protein expression of MACC1, HGF and c-Met was significantly higher in human gastric cancer tissues compared with adjacent normal tissues. Positive expression of MACC1 and c-Met in gastric cancer tissues had no correlation with the sex, age, tumor location and peritoneal metastasis of patients, but was significantly correlated with tumor size, depth of tumor invasion, lymph node metastasis, TNM stage, histological differentiation, and overall (5 years) and disease-free survival (5 years). Positive expression of each MACC1, HGF and c-Met protein was demonstrated to be positively correlated with each other in human gastric cancer tissues. Western blotting results confirmed that MACC1 protein was overexpressed in MACC1-overexpressing lentivirus-infected HSCs. Overexpression of MACC1 significantly increased HGF, MMP-2, MMP-9 and ?-SMA expression levels in HSCs. Results from the Transwell assays indicated an increase in the number of MKN45 or MKN74 cells migrating towards MACC1-overexpressing HSCs, compared with control HSCs. These findings suggested that MACC1 may regulate the expression of HGF, MMP-2 and MMP-9 in HSCs, and may thus promote migration and invasion of gastric carcinoma cells. MACC1, HGF and c-Met might cooperatively participate in the malignant progression of gastric cancer. In conclusion, MACC1 might serve as a useful molecular target for the diagnosis, treatment and prognosis of gastric cancer.

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A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients.

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A common variant of the MACC1 gene is significantly associated with overall survival in colorectal cancer patients.

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