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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

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...

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Autores principales: Macartney-Coxson, Donia P, Hood, Kylie A, Shi, Hong-jun, Ward, Teresa, Wiles, Anna, O'Connor, Rosemary, Hall, David A, Lea, Rod A, Royds, Janice A, Stubbs, Richard S, Rooker, Serena
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2488356/
https://www.ncbi.nlm.nih.gov/pubmed/18590575
http://dx.doi.org/10.1186/1471-2407-8-187
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author Macartney-Coxson, Donia P
Hood, Kylie A
Shi, Hong-jun
Ward, Teresa
Wiles, Anna
O'Connor, Rosemary
Hall, David A
Lea, Rod A
Royds, Janice A
Stubbs, Richard S
Rooker, Serena
author_facet Macartney-Coxson, Donia P
Hood, Kylie A
Shi, Hong-jun
Ward, Teresa
Wiles, Anna
O'Connor, Rosemary
Hall, David A
Lea, Rod A
Royds, Janice A
Stubbs, Richard S
Rooker, Serena
author_sort Macartney-Coxson, Donia P
collection PubMed
description 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). CONCLUSION: Our data confirm that genes on 8p21-22 are dysregulated during colorectal cancer progression. Interestingly, however, instead of harbouring a single candidate colorectal metastasis suppressor 8p21-22 appears to be a hot-spot for tumour progression, encoding at least 13 genes with a putative role in carcinoma development. Thus, we propose that this region of 8p comprises a metastatic susceptibility locus involved in tumour progression whose disruption increases metastatic potential.
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spelling pubmed-24883562008-07-29 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 Macartney-Coxson, Donia P Hood, Kylie A Shi, Hong-jun Ward, Teresa Wiles, Anna O'Connor, Rosemary Hall, David A Lea, Rod A Royds, Janice A Stubbs, Richard S Rooker, Serena BMC Cancer Research Article 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). CONCLUSION: Our data confirm that genes on 8p21-22 are dysregulated during colorectal cancer progression. Interestingly, however, instead of harbouring a single candidate colorectal metastasis suppressor 8p21-22 appears to be a hot-spot for tumour progression, encoding at least 13 genes with a putative role in carcinoma development. Thus, we propose that this region of 8p comprises a metastatic susceptibility locus involved in tumour progression whose disruption increases metastatic potential. BioMed Central 2008-07-01 /pmc/articles/PMC2488356/ /pubmed/18590575 http://dx.doi.org/10.1186/1471-2407-8-187 Text en Copyright © 2008 Macartney-Coxson et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Macartney-Coxson, Donia P
Hood, Kylie A
Shi, Hong-jun
Ward, Teresa
Wiles, Anna
O'Connor, Rosemary
Hall, David A
Lea, Rod A
Royds, Janice A
Stubbs, Richard S
Rooker, Serena
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2488356/
https://www.ncbi.nlm.nih.gov/pubmed/18590575
http://dx.doi.org/10.1186/1471-2407-8-187
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