Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases

Houlston, Richard S.; Bevan, Steve; Williams, Andrew N; Young, Joanne; Dunlop, Malcolm G.; Rozen, Paul; Eng, Charis; Markie, David; Woodford-Richens, Kelly; Rodrı́guez-Bigas, Miguel A.; Leggett, Barbara A.; Neale, Kay; Phillips, R. K. S.; Sheridan, E.; Hodgson, Shirley; Iwama, Takeo; Eccles, Diana M.; Bodmer, W F; Tomlinson, Ian

doi:10.1093/hmg/7.12.1907

Cited by 125 publications

(85 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Exon-by-exon amplification of the 11 exons of SMAD4 (encompassing the coding sequence and all intron/exon boundaries) was done on DNA from patients with a single allelic loss of SMAD4 and negative SMAD4 expression, as previously described (33). The untranslated regions of SMAD4 in nine gastric carcinoma cell lines were also amplified (see Supplementary Table S1 for primers and PCR conditions).…”

Section: Methodsmentioning

confidence: 99%

Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

Wang

Kim

Lee

et al. 2007

Clinical Cancer Research

100

View full text Add to dashboard Cite

Purpose: Mothers against decapentaplegic homologue 4 (SMAD4) is a tumor suppressor gene associated with gastrointestinal carcinogenesis. The aim of the present study is to more precisely characterize its role in the development and progression of human gastric carcinoma. Experimental Design: The expression of SMAD4 was investigated in 283 gastric adenocarcinomas and related lesions, as well as in 9 gastric carcinoma cell lines. We also analyzed the methylation status of SMAD4 gene by using methylation-specific PCR, examined loss of heterozygosity (LOH) of this gene locus by using a vicinal marker, and detected exon mutation of SMAD4 through exon-by-exon amplification. Moreover, we assessed whether MG132, a proteasome inhibitor, affected the SMAD4 protein level. Results: We found loss of SMAD4 protein expression in the cytoplasm (36 of 114, 32%) and in the nucleus (46 of 114, 40%) of gastric cancer cells. The loss of nuclear SMAD4 expression in primary tumors correlated significantly with poor survival, and was an independent prognostic marker in multivariate analysis.We also found a substantial decrease in SMAD4 expression at both the RNA and protein level in several human gastric carcinoma cell lines. In addition, we found that LOH (20 of 70, 29%) and promoter hypermethylation (4 of 73, 5%) were associated with the loss of SMAD4 expression. SMAD4 protein levels were also affected in certain gastric carcinoma cell lines following incubation with MG132. Conclusion: Taken together, our results indicate that the loss of SMAD4, especially loss of nuclear SMAD4 expression, is involved in gastric cancer progression. The loss of SMAD4 in gastric carcinomas was due to several mechanisms, including LOH, hypermethylation, and proteasome degradation.

show abstract

Section: Methodsmentioning

confidence: 99%

Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

Wang

Kim

Lee

et al. 2007

Clinical Cancer Research

100

View full text Add to dashboard Cite

show abstract

“…Each patient had been screened previously for either SMAD4 (JPS) or LKB1 (PJS) mutations, but none had been found Houlston et al, 1998;Ylikorkala et al, 1999). Also chosen for screening were 49 colorectal cancer cell lines (C10, C32, C70, C75, C80, C84, C99, C106, C125, CAC02, COLO201, COLO205, COLO206, COLO320, COLO678, COLO741, CX1, DLD1, GP2D, GP5D, HCA46, HCA7, HCT8, HCT15, HCT116, HRA19, HT29, HT55, LIM1863, LOVO, LS174T, LS180, LS411, LS1034, PC/JW, SKC01, SW48, SW403, SW480, SW620, SW837, SW948, SW1222, SW1417, T84, VACO4A, VACO4S, VACO5, VACO10).…”

Section: Methodsmentioning

confidence: 99%

CDX2 mutations do not account for juvenile polyposis or Peutz–Jeghers syndrome and occur infrequently in sporadic colorectal cancers

Woodford-Richens¹,

Halford

Rowan³

et al. 2001

Br J Cancer

View full text Add to dashboard Cite

Peutz–Jeghers syndrome (PJS) and juvenile polyposis (JPS) are both characterized by the presence of hamartomatous polyps and increased risk of malignancy in the gastrointestinal tract. Mutations of the LKB1 and SMAD4 genes have been shown recently to cause a number of PJS and JPS cases respectively, but there remains considerable uncharacterized genetic heterogeneity in these syndromes, particularly JPS. The mouse homologue of CDX2 has been shown to give rise to a phenotype which includes hamartomatous-like polyps in the colon and is therefore a good candidate for JPS and PJS cases which are not accounted for by the SMAD4 and LKB1 genes. By analogy with SMAD4 CDX2 is also a candidate for somatic mutation in sporadic colorectal cancer. We have screened 37 JPS families/cases without known SMAD4 mutations, 10 Peutz-Jeghers cases without known LKB1 mutations and 49 sporadic colorectal cancers for mutations in CDX2 . Although polymorphic variants and rare variants of unlikely significance were detected, no pathogenic CDX2 mutations were found in any case of JPS or PJS, or in any of the sporadic cancers. © 2001 Cancer Research Campaign www.bjcancer.com

show abstract

“…The same approach was used to amplify SMAD4, p53 and Caspase-10. Primers to amplify SMAD4 exons 1 and 10 were based on those previously reported in [18], and the remaining exons were amplified with newly-designed primers (primer sequences are given upon request). The p53 mutational hotspot (exons 5-8), was amplified using the primers from the Operon kit (Operon Technologies, Inc. Atlantic City.…”

Section: Polymerase Chain Reaction-single-strand Conformation Polymormentioning

confidence: 99%

E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients

Oliveira

Ferreira

Nabais

et al. 2004

European Journal of Cancer

View full text Add to dashboard Cite

Approximately 30% of all hereditary diffuse gastric cancer (HDGC) families carry CDH1 germline mutations. The other two thirds remain genetically unexplained and are probably caused by alterations in other genes. Using polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP)/sequencing, we screened 32 Portuguese families with a history of gastric cancer and 23 patients with early onset gastric cancer for CDH1 germline mutations. In probands negative for CDH1 mutations, we screened genes involved in hereditary cancer syndromes in which gastric cancer may be one of the component tumours, namely p53 (Li-Fraumeni Syndrome) and hMLH1 and hMSH2 (HNPCC). We also screened in these patients for mutations in Caspase-10, a gene inactivated in sporadic gastric cancer, and SMAD4, a gene whose inactivation in mice is associated with signet-ring cell carcinoma of the stomach. One of the families fulfilling the HDGC criteria harboured a CDH1 germline mutation, and one of the families with incomplete criteria harboured a p53 germline mutation. No mutations were identified in hMLH1 and hMSH2, and only sequence variants were found in SMAD4 and Caspase-10. The present work reports for the first time CDH1 germline mutations in Portuguese gastric cancer families, and highlights the need for p53 mutation screening in families lacking CDH1 germline mutations, in a country with one of the highest incidences of gastric cancer in the world. No evidence was found for a role of germline mutations in SMAD4 and Caspase-10 in families lacking CDH1 mutations.

show abstract

Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases

Cited by 125 publications

References 14 publications

Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression

CDX2 mutations do not account for juvenile polyposis or Peutz–Jeghers syndrome and occur infrequently in sporadic colorectal cancers

E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients

Contact Info

Product

Resources

About