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

Iacopetta, Barry; Welch, John L.; Soong, Richie; House, A. K.; Zhou, Xiaoping; Hamelin, Richard

doi:10.1002/(sici)1096-9896(199804)184:4<390::aid-path1230>3.0.co;2-q

Cited by 67 publications

(24 citation statements)

References 28 publications

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“…In sporadic CRCs, SMAD4 and TGFBR2 mutations are found in approximately 10% and 15% of patients, respectively (9)(10)(11)(12). TGFBR2 mutations are particularly prevalent in microsatellite unstable (MSI) tumors, with approximately 80% of such cases harboring frameshift mutations at a poly-adenosine tract in exon 4 (13).…”

Section: Introductionmentioning

confidence: 99%

SMAD2,SMAD3andSMAD4Mutations in Colorectal Cancer

et al. 2013

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Activation of the canonical TGF-b signaling pathway provides growth inhibitory signals in the normal intestinal epithelium. Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members TGFBR2 and SMAD4, but to what extent mutations in SMAD2 or SMAD3 contribute to tumorigenesis is unclear. A cohort of 744 primary CRCs and 36 CRC cell lines were sequenced for SMAD4, SMAD2, and SMAD3 and analyzed for allelic loss by single-nucleotide polymorphism (SNP) microarray analysis. Mutation spectra were compared between the genes, the pathogenicity of mutations was assessed, and relationships with clinicopathologic features were examined. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. A significant overrepresentation of two genetic hits was detected for SMAD4 and SMAD3, consistent with these genes acting as tumor suppressors. SMAD4 mutations were associated with mucinous histology. The mutation spectra of SMAD2 and SMAD3 were highly similar to that of SMAD4, both in mutation type and location within the encoded proteins. In silico analyses suggested the majority of the mutations were pathogenic, with most missense changes predicted to reduce protein stability or hinder SMAD complex formation. The latter altered interface residues or disrupted the phosphorylation-regulated Ser-Ser-XSer motifs within SMAD2 and SMAD3. Functional analyses of selected mutations showed reductions in SMAD3 transcriptional activity and SMAD2-SMAD4 complex formation. Joint biallelic hits in SMAD2 and SMAD3 were overrepresented and mutually exclusive to SMAD4 mutation, underlining the critical roles of these three proteins within the TGF-b signaling pathway. Cancer Res; 73(2); 725-35. Ó2012 AACR.

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Section: Introductionmentioning

confidence: 99%

SMAD2,SMAD3andSMAD4Mutations in Colorectal Cancer

et al. 2013

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“…Rijcken et al (21) reported that adenomas in hereditary nonpolyposis colorectal cancer patients had increased susceptibility to malignant conversion than sporadic adenomas found in control patients, specifically on the right-side colon. Mechanisms similar to hereditary nonpolyposis colorectal cancer may be engaged in carcinogenesis in the right-side colon of old people (22)(23)(24)(25).…”

Section: Discussionmentioning

confidence: 99%

The Malignant Potential of Freshly Developed Colorectal Polyps According to Age

Yamaji

Mitsushima

Yoshida

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Although malignant colorectal neoplasms are found more frequently in older population, polyps found at one-time colonoscopy may be a mixture of lesions that developed at various earlier ages. Newly developed adenomas found at the follow-up colonoscopies will reflect the exact relation between malignant potential and the age of development of colorectal polyps. Methods: The results of 44,065 follow-up colonoscopies on 11,912 subjects were analyzed. The proportion of invasive cancer or high-grade dysplasia among all neoplasms, ''proportion of malignancy,'' was evaluated in relation to age groups (young: <50 years old; middle: 50-59 years old; and old: z60 years old).

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“…The direct association between increased transcription of MLH1 and MSH2 with MSI might suggest that their activity is at least in part co-ordinated, perhaps as an attempt to control the higher mutation rate in MSI-H. An intriguing finding was the reduction in p53 transcription in MSI-H compared to normal bowel, and MSS or MSI-L cancers. While studies on p53 mutation in MSI have shown conflicting results, there is a consensus that p53 has an inverse relationship with MSI (Cottu et al, 1996;Breivik et al, 1997;Olschwang et al, 1997;Forster et al, 1998;Iacopetta et al, 1998). The basis for the apparent reduced rate of p53 mutations in the higher 'mutator' phenotype of MSI-H has remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…However, the results from different studies should be interpreted with caution, taking into consideration the processes of tissue fixation and staining, the antibodies employed and the scoring technique adopted. For example, differences in reported rates of p53 mutation can be accounted for by the inconsistent measurement of stained cells that varied from 5 to 30% in determining if a cancer is mutated or not (Kim et al, 1994;Ilyas et al, 1996;Iacopetta et al, 1998). Moreover, p53 overexpression can occur in the absence of mutation due to the accumulation of wild-type p53 in cancer cells (Cripps et al, 1994;Dix et al, 1994), again highlighting the potential for mis-assigning p53 mutations in MSI cancers if mutation is based on overexpression of p53 protein.…”

Section: Discussionmentioning

confidence: 99%

“…Since overexpression of MLH1 and MSH2 induces apoptosis (Zhang et al, 1999), the relationships between these genes and the mutation and function of the tumour-suppressor gene p53 have been of interest. There appears to be an inverse relationship between MSI 'severity' (status) and p53 mutation (Cottu et al, 1996;Breivik et al, 1997;Olschwang et al, 1997;Forster et al, 1998;Iacopetta et al, 1998), which seems paradoxical as a greater rate of p53 mutation in higher 'mutator phenotype' MSI-H cancers might be expected. The mechanism underlying this effect is unclear but might relate to the degree of DNA methylation and consequently gene activity in the MMR genes (Cunningham et al, 1998;Kuismanen et al, 1999), although this has not been described.…”

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confidence: 99%

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Activity (transcription) of the genes for MLH1, MSH2 and p53 in sporadic colorectal tumours with micro-satellite instability

et al. 2004

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Micro-satellite instability (MSI) is relevant in the management of colorectal cancers (CRC) and relies on analysis of gene mutations, or production of the proteins involved in DNA mismatch repair (e.g. MLH1, MSH2). p53 mutation is also relevant in MSI, but high-level CRC (MSI-H) demonstrate fewer mutations than low-level (MSI-L) or stable (MSS) cancers. Recently, the importance of gene activity (transcription) in MSI has been identified, where rather than being mutated genes have been downregulated. In this study, 67 sporadic CRC and eight samples of normal bowel were analysed for MSI status (by SSCP) and levels of MLH1, MSH2 and p53 gene transcription (by RT -PCR and scanning densitometry). Micro-satellite instability correlated with gender and site, with more MSI-H CRC in females (Po0.02) and in the right colon (Po0.04). In MSI-H, p53 transcription was markedly reduced (Po0.003). Compared to normal bowel, MLH1 transcription was elevated in all cancers (Po0.01), while MSH2 transcription was elevated only in MSI-H (Po0.04). There was a direct correlation between MLH1 and MSH2 transcription (Po0.001). Although fewer mutations are reported in MSI-H than MSI-L/MSS, these results suggest that reduced p53 transcription might account for decreased tumour suppression in MSI-H. The direct correlation between MLH1 and MSH2 transcription suggests that control of these genes might be coordinated.

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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

Cited by 67 publications

References 28 publications

SMAD2,SMAD3andSMAD4Mutations in Colorectal Cancer

SMAD2,SMAD3andSMAD4Mutations in Colorectal Cancer

The Malignant Potential of Freshly Developed Colorectal Polyps According to Age

Activity (transcription) of the genes for MLH1, MSH2 and p53 in sporadic colorectal tumours with micro-satellite instability

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