Abstract
BackgroundDespite identification of the major genes and pathways involved in the development of colorectal cancer (CRC), it has become obvious that several steps in these pathways might be bypassed by other as yet unknown genetic events that lead towards CRC. Therefore we wanted to improve our understanding of the genetic mechanisms of CRC development.MethodsWe used microarrays to identify novel genes involved in the development of CRC. Real time PCR was used for mRNA expression as well as to search for chromosomal abnormalities within candidate genes. The correlation between the expression obtained by real time PCR and the presence of the KRAS mutation was investigated.ResultsWe detected significant previously undescribed underexpression in CRC for genes SLC26A3, TPM1 and DCN, with a suggested tumour suppressor role. We also describe the correlation between TPM1 and DCN expression and the presence of KRAS mutations in CRC. When searching for chromosomal abnormalities, we found deletion of the TPM1 gene in one case of CRC, but no deletions of DCN and SLC26A3 were found.ConclusionOur study provides further evidence of decreased mRNA expression of three important tumour suppressor genes in cases of CRC, thus implicating them in the development of this type of cancer. Moreover, we found underexpression of the TPM1 gene in a case of CRCs without KRAS mutations, showing that TPM1 might serve as an alternative path of development of CRC. This downregulation could in some cases be mediated by deletion of the TPM1 gene. On the other hand, the correlation of DCN underexpression with the presence of KRAS mutations suggests that DCN expression is affected by the presence of activating KRAS mutations, lowering the amount of the important tumour suppressor protein decorin.
Highlights
Despite identification of the major genes and pathways involved in the development of colorectal cancer (CRC), it has become obvious that several steps in these pathways might be bypassed by other as yet unknown genetic events that lead towards CRC
We found no change in expression of the tropomysin 1 (TPM1) gene in CRC cases with a mutation in KRAS, in comparison with underexpression of the TPM1 gene in CRCs without activating KRAS mutations (p < 0,05) (Figure 3)
We described a correlation between TPM1 and DCN expression and the presence of KRAS mutations in CRC
Summary
Despite identification of the major genes and pathways involved in the development of colorectal cancer (CRC), it has become obvious that several steps in these pathways might be bypassed by other as yet unknown genetic events that lead towards CRC. Even though major genes involved in the development of colorectal cancer have been identified, interestingly most of them have shown only limited value in clinical use [6]. They have recently been shown to be involved in the response of CRCs to cetuximab, suggesting a better response of patients without KRAS mutations in CRCs [9,10] This shows that several steps in CRC development might be bypassed by other as yet unknown genetic events that lead towards CRC. We wanted to improve our understanding of the genetic mechanisms of CRC development This might identify new potential tumour markers useful for clinical practice
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