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Mutations in TGFbeta-RII and BAX mediate tumor progression in the later stages of colorectal cancer with microsatellite instability.

Yashiro M, Hirakawa K, Boland CR - BMC Cancer (2010)

Bottom Line: In this study, early stage CRCs were examined for frameshift mutations in these target genes, and compared with late stage tumors and CRC cell lines.There is a statistical association (p = 0.014) between mutation in any one gene and tumor stage.TGFbetaRII, BAX, hMSH3 and hMSH6 mutations are relatively late events in the genesis of MSI CRCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan. m9312510@med.osaka-cu.ac.jp

ABSTRACT

Background: Microsatellite instability (MSI) occurs in 15% of colorectal cancers (CRC). The genetic targets for mutation in the MSI phenotype include somatic mutations in the transforming growth factor beta receptor typeII (TGFbetaRII), BAX, hMSH3 and hMSH6. It is not clear how mutations of these genes mediate tumor progression in the MSI pathway, and the temporal sequence of these mutations remains uncertain. In this study, early stage CRCs were examined for frameshift mutations in these target genes, and compared with late stage tumors and CRC cell lines.

Methods: We investigated 6 CRC cell lines and 71 sporadic CRCs, including 61 early stage cancers and 10 late stage cancers. Mutations of repetitive mononucleotide tracts in the coding regions of TGFbetaRII, BAX, hMSH3, hMSH6, IGFIIR and Fas antigen were identified by direct sequencing.

Results: Thirteen (18.3%) of 71 CRC, including 9/61 (14.7%) early stage cancers and 4/10 (40%) late stage cancers, were identified as MSI and analyzed for frameshift mutations. No mutation in the target genes was observed in any of the 9 early stage MSI CRCs. In contrast, frameshift mutations of TGFbetaRII, BAX, hMSH3 and hMSH6 were present in 3/4 late stage MSI tumors. There is a statistical association (p = 0.014) between mutation in any one gene and tumor stage.

Conclusions: TGFbetaRII, BAX, hMSH3 and hMSH6 mutations are relatively late events in the genesis of MSI CRCs. The frameshift mutations in these target genes might mediate progression from early to late stage cancer, rather than mediating the adenoma to carcinoma transition.

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Related in: MedlinePlus

Frameshift mutations in CRCs with MSI. The genes are indicated at the left. Arrowheads indicate 1 bp deletion mutations in tumors. T and N refer to DNA from tumors and corresponding normal tissues, respectively.
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Figure 2: Frameshift mutations in CRCs with MSI. The genes are indicated at the left. Arrowheads indicate 1 bp deletion mutations in tumors. T and N refer to DNA from tumors and corresponding normal tissues, respectively.

Mentions: Thirteen of 71(18.3%) sporadic CRCs, including 9/61 (14.7%) early stage CRCs and 4/10 (40%) late stage cancers were identified as MSI tumors (Table 1), and these tumors were analyzed for frameshift mutations. Mutations in the noncoding region of β-catenin, which contains a (T)27 sequence, were present in 7/9 MSI early stage CRCs (patients 1-9) and 3/4 MSI-H late stage CRCs (patients 10-13) (Figure 2A). No frameshift mutations in the target genes were present in any MSI early stage CRCs. In contrast, frameshift mutations of TGFβRII, BAX, hMSH3 and hMSH6 were present in 3/4 late stage CRCs (Table 1). A significant difference (p = 0.014) was found in the frequency of frameshift mutations between early stage and. late stage (Table 2). TGFβRII and BAX mutations were found in the late stage tumors of patients 11 and 10, respectively (Figure 2B). hMSH3 mutations were present in patients 11 and 12, and an hMSH6 mutation was found in patient 12. Each mutation was found to be a 1 bp deletion in the polynucleotide tract (Figure 3). No frameshift mutations in IGFIIR or Fas antigen were found in any CRC.


Mutations in TGFbeta-RII and BAX mediate tumor progression in the later stages of colorectal cancer with microsatellite instability.

Yashiro M, Hirakawa K, Boland CR - BMC Cancer (2010)

Frameshift mutations in CRCs with MSI. The genes are indicated at the left. Arrowheads indicate 1 bp deletion mutations in tumors. T and N refer to DNA from tumors and corresponding normal tissues, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927997&req=5

Figure 2: Frameshift mutations in CRCs with MSI. The genes are indicated at the left. Arrowheads indicate 1 bp deletion mutations in tumors. T and N refer to DNA from tumors and corresponding normal tissues, respectively.
Mentions: Thirteen of 71(18.3%) sporadic CRCs, including 9/61 (14.7%) early stage CRCs and 4/10 (40%) late stage cancers were identified as MSI tumors (Table 1), and these tumors were analyzed for frameshift mutations. Mutations in the noncoding region of β-catenin, which contains a (T)27 sequence, were present in 7/9 MSI early stage CRCs (patients 1-9) and 3/4 MSI-H late stage CRCs (patients 10-13) (Figure 2A). No frameshift mutations in the target genes were present in any MSI early stage CRCs. In contrast, frameshift mutations of TGFβRII, BAX, hMSH3 and hMSH6 were present in 3/4 late stage CRCs (Table 1). A significant difference (p = 0.014) was found in the frequency of frameshift mutations between early stage and. late stage (Table 2). TGFβRII and BAX mutations were found in the late stage tumors of patients 11 and 10, respectively (Figure 2B). hMSH3 mutations were present in patients 11 and 12, and an hMSH6 mutation was found in patient 12. Each mutation was found to be a 1 bp deletion in the polynucleotide tract (Figure 3). No frameshift mutations in IGFIIR or Fas antigen were found in any CRC.

Bottom Line: In this study, early stage CRCs were examined for frameshift mutations in these target genes, and compared with late stage tumors and CRC cell lines.There is a statistical association (p = 0.014) between mutation in any one gene and tumor stage.TGFbetaRII, BAX, hMSH3 and hMSH6 mutations are relatively late events in the genesis of MSI CRCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan. m9312510@med.osaka-cu.ac.jp

ABSTRACT

Background: Microsatellite instability (MSI) occurs in 15% of colorectal cancers (CRC). The genetic targets for mutation in the MSI phenotype include somatic mutations in the transforming growth factor beta receptor typeII (TGFbetaRII), BAX, hMSH3 and hMSH6. It is not clear how mutations of these genes mediate tumor progression in the MSI pathway, and the temporal sequence of these mutations remains uncertain. In this study, early stage CRCs were examined for frameshift mutations in these target genes, and compared with late stage tumors and CRC cell lines.

Methods: We investigated 6 CRC cell lines and 71 sporadic CRCs, including 61 early stage cancers and 10 late stage cancers. Mutations of repetitive mononucleotide tracts in the coding regions of TGFbetaRII, BAX, hMSH3, hMSH6, IGFIIR and Fas antigen were identified by direct sequencing.

Results: Thirteen (18.3%) of 71 CRC, including 9/61 (14.7%) early stage cancers and 4/10 (40%) late stage cancers, were identified as MSI and analyzed for frameshift mutations. No mutation in the target genes was observed in any of the 9 early stage MSI CRCs. In contrast, frameshift mutations of TGFbetaRII, BAX, hMSH3 and hMSH6 were present in 3/4 late stage MSI tumors. There is a statistical association (p = 0.014) between mutation in any one gene and tumor stage.

Conclusions: TGFbetaRII, BAX, hMSH3 and hMSH6 mutations are relatively late events in the genesis of MSI CRCs. The frameshift mutations in these target genes might mediate progression from early to late stage cancer, rather than mediating the adenoma to carcinoma transition.

Show MeSH
Related in: MedlinePlus