Mutations of the Transforming Growth Factor-β Type II Receptor Gene and Genomic Instability in Hereditary Nonpolyposis Colorectal Cancer

Lu, Shi‐Long; Akiyama, Yoshimitsu; Nagasaki, Hiromi; Saitoh, Kiyoshi; Yuasa, Yasuhito

doi:10.1006/bbrc.1995.2644

Cited by 121 publications

(80 citation statements)

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“…Mutations in the TGFb RII gene were reported recently to occur in human cancers of the colon Lu et al, 1995;Parsons et al, 1995), stomach (Park et al, 1994), endometrium , and head and neck (GarrigueAntar et al, 1995). These and other observations are consistent with the hypothesis that TGFb RII is a tumor suppressor gene whose mutational inactivation is important in human carcinogenesis (Sun et al, 1994;Wang et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we determined the intron sequences¯anking the seven exons and produced eight intron based primer pairs for mutation analysis of the entire coding region of the TGFb RII gene. Since previous studies of colorectal cancer have focused on tumors with MI Lu et al, 1995;Parsons et al, 1995), we analysed 30 sporadic colorectal cancers by PCR ± SSCP and DNA sequencing for mutations in the TGFb RII gene in genomic DNA samples.…”

Section: Introductionmentioning

confidence: 99%

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Mutation analysis of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human colon cancer using genomic DNA and Intron primers

Takenoshita

Tani²,

Nagashima

et al. 1997

Oncogene

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Mutations in the transforming growth factor beta type II receptor (TGFb RII) gene have been detected in several human cancers exhibiting microsatellite instability. To extend analyses of this gene, we previously investigated the exon-intron organization of the TGFb RII gene and de®ned seven exons and¯anking intron sequences. In this study, we further determined the nucleotide sequences surrounding these seven exons and designed eight sets of intron-based primers to examine the entire coding region of the TGFb RII gene. Using these primers, we screened genomic DNA sequences from 30 sporadic colorectal cancers for mutations of the TGFb RII gene. TGFb RII mutations were detected in two of 30 tumors and both displayed microsatellite instability. One had a deletion in a polyadenine tract in exon 3 and the other had a point mutation in the kinase domain located in exon 7. There were no mutations in exons 1, 2, 4, 5 and 6. These results further implicate the polyadenine tract and kinase domain as mutational hotspots in the TGFb RII gene in cells with genomic instability and suggest that TGFb RII gene mutations occur rarely in cells lacking genomic instability.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutation analysis of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human colon cancer using genomic DNA and Intron primers

Takenoshita

Tani²,

Nagashima

et al. 1997

Oncogene

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“…Candidate substrates include a WDdomain protein associated with and phosphorylated by RII (Chen et al, 1995) and several novel human genes related to a Drosophila gene called mad which are either mutated or deleted in colon cancer (Riggins et al, 1996). Experiments demonstrating mutational inactivation of (Markowitz et al, 1995a;Lu et al, 1995) and growth suppression by the RII (Sun et al, 1994;Wang et al, 1995) have raised the hypothesis that RII is a tumor suppressor gene.…”

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confidence: 99%

“…RII mutations have been predominantly frameshifts in nucleotide repeats in colon and gastric cancers with microsatellite instability (MI, see Parsons et al, 1995;Markowitz et al, 1995;Lu et al, 1995;Wang et al, 1995;Myero et al, 1995). These mutations are characteristic of the mismatch repair de®cit found in hereditary non-polyposis colon cancers which have MI and frequent mutations in the hMSH2 and hMLH1 genes (Liu et al, 1996).…”

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Mutation analysis of the transforming growth factor-β type II receptor in human cell lines resistant to growth inhibition by transforming growth factor-β

et al. 1997

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The transforming growth factor-b (TGF-b) binds the type II TGF-b growth factor receptor (RII) to inhibit the growth of most epithelial tissues. Most human colon and gastric cancers with microsatellite instability (MI) have frameshift mutations in polynucleotide repeats within the RII coding region; these mutations truncate the receptor protein and disable the serine/threonine kinase to produce TGF-b resistance. To further investigate the type, frequency and tissue distribution of RII mutations, we selected 24 human cancer cell lines from various tissues which were previously reported to be resistant to the inhibitory e ects of TGF-b. We developed protocols for non-isotopic SSCP analysis of PCR products from genomic DNA samples, and we tested them for microsatellite instability. PCR ± SSCP analysis followed by DNA sequencing identi®ed deletion mutations in the exon 3 poly-adenine tract in three colon tumor cell lines: LS174T and SW48 had a single base deletion and LS411 had a two base deletion. Among the 24 previously unreported cell lines, only these three demonstrated microsatellite instability. These and other recent data indicate that RII mutations are essentially con®ned to colon and gastric cancers with microsatellite instability. The narrow spectrum of tissues containing RII mutations illustrates the complexity of genetic checkpoints in human carcinogenesis.

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Mutation of the transforming growth factor-β type II receptor gene in right-sided colorectal cancer: relationship to clinicopathological features and genetic alterations

et al. 1998

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Mutations of the Transforming Growth Factor-β Type II Receptor Gene and Genomic Instability in Hereditary Nonpolyposis Colorectal Cancer

Cited by 121 publications

References 0 publications

Mutation analysis of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human colon cancer using genomic DNA and Intron primers

Mutation analysis of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human colon cancer using genomic DNA and Intron primers

Mutation analysis of the transforming growth factor-β type II receptor in human cell lines resistant to growth inhibition by transforming growth factor-β

Mutation of the transforming growth factor-β type II receptor gene in right-sided colorectal cancer: relationship to clinicopathological features and genetic alterations

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