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- Title
Metastatic susceptibility locus, an 8p hot-spot for tumour progression disrupted in colorectal liver metastases: 13 candidate genes examined at the DNA, mRNA and protein level.
- Authors
Macartney-Coxson, Donia P.; Hood, Kylie A.; Hong-jun Shi; Ward, Teresa; Wiles, Anna; O'Connor, Rosemary; Hall, David A.; Lea, Rod A.; Royds, Janice A.; Stubbs, Richard S.; Rooker, Serena
- Abstract
Background: Mortality from colorectal cancer is mainly due to metastatic liver disease. Improved understanding of the molecular events underlying metastasis is crucial for the development of new methods for early detection and treatment of colorectal cancer. Loss of chromosome 8p is frequently seen in colorectal cancer and implicated in later stage disease and metastasis, although a single metastasis suppressor gene has yet to be identified. We therefore examined 8p for genes involved in colorectal cancer progression. Methods: Loss of heterozygosity analyses were used to map genetic loss in colorectal liver metastases. Candidate genes in the region of loss were investigated in clinical samples from 44 patients, including 6 with matched colon normal, colon tumour and liver metastasis. We investigated gene disruption at the level of DNA, mRNA and protein using a combination of mutation, semi-quantitative real-time PCR, western blotting and immunohistochemical analyses. Results: We mapped a 2 Mb region of 8p21-22 with loss of heterozygosity in 73% of samples; 8/ 11 liver metastasis samples had loss which was not present in the corresponding matched primary colon tumour. 13 candidate genes were identified for further analysis. Both up and down-regulation of 8p21-22 gene expression was associated with metastasis. ADAMDEC1 mRNA and protein expression decreased during both tumourigenesis and tumour progression. Increased STC1 and LOXL2 mRNA expression occurred during tumourigenesis. Liver metastases with low DcR1/ TNFRSF10C mRNA expression were more likely to present with extrahepatic metastases (p = 0.005). A novel germline truncating mutation of DR5/TNFRSF10B was identified, and DR4/ TNFRSF10A SNP rs4872077 was associated with the development of liver metastases (p = 0.02).
- Subjects
COLON cancer; CANCER susceptibility; LIVER metastasis; LIVER cancer; DNA; MESSENGER RNA; CARCINOGENESIS
- Publication
BMC Cancer, 2008, Vol 8, p1
- ISSN
1471-2407
- Publication type
Article
- DOI
10.1186/1471-2407-8-187