The clinicopathological features of gastric carcinomas with micro-satellite instability may be mediated by mutations of different ‘target genes’. A study of the TGFβRII, IGFII R and BAX genes

Oliveira, Carla; Seruca, Raquel; Seixas, Mário; Sobrinho‐Simöes, Manuel

doi:10.1097/00008469-199908000-00034

Cited by 47 publications

(84 citation statements)

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“…Also, MSI-H tumors tended to represent a lower clinical stage than LOH-N/LOH tumors. These results are in agreement with earlier observations [9,11,[39][40][41][42][43].…”

Section: Discussionsupporting

confidence: 94%

“…MSI-H has been associated with expanding growth, a high number of tumor-infiltrating lymphocytes, poor differentiation, lower clinical stage, intestinal type, lower likelihood of distant metastases, older age at detection, and better prognosis [9,11,[40][41][42][43]. LOH has been shown to relate to cancer progression, where a transition from LOH-L to LOH-H is thought to reflect an increase in chromosomal instability during tumor advancement [7,11,12].…”

Section: Discussionmentioning

confidence: 99%

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Differences in genomic instability between intestinal- and diffuse-type gastric cancer

Vauhkonen

Sajantila

et al. 2005

Gastric Cancer

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“…Also, MSI-H tumors tended to represent a lower clinical stage than LOH-N/LOH tumors. These results are in agreement with earlier observations [9,11,[39][40][41][42][43].…”

Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Differences in genomic instability between intestinal- and diffuse-type gastric cancer

Vauhkonen

Sajantila

et al. 2005

Gastric Cancer

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“…Available neoplastic lesions from family probands and early onset gastric cancer patients were studied for MSI using a panel of 5 dinucleotide repeat markers and/ or BAT 26 [19]. The PCR products from tumour versus constitutional DNA were labelled by [aÀ 32 P] deoxycytidine triphosphate (dCTP) during the amplification reaction, separated by electrophoresis in 6% denaturing polyacrylamide gels, at a constant current over approximately 3 h, and visualised by autoradiography.…”

Section: Microsatellite Instability Analysismentioning

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

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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.

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“…2 Mutation at the poly(A) 10 repeat sequence (BAT-RII) in the extracellular domain of TGF␤RII (with concomitant decreases in protein expression) is strongly correlated with the MSI phenotype and has been demonstrated in MSI-positive colon and gastric carcinomas. [3][4][5] Insertion of an extra GT into the coding poly(GT) 3 microsatellite region of TGF␤RII site also has been documented in colorectal and gastric carcinomas. 2 The BAT-26 region, a repeat of 26 deoxyadenosines located in intron 5 of hMSH2, is a highly accurate and sensitive indicator of MSI in colorectal and gastric carcinomas.…”

mentioning

confidence: 99%

Microsatellite instability and gene mutations in transforming growth factor‐beta type II receptor are absent in small bowel carcinoid tumors

Kidd

Eick

Shapiro

et al. 2005

Cancer

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BACKGROUND Microsatellite instability (MSI) with concomitant mutations in the coding region of transforming growth factor‐beta type II receptor (TGFβRII) results in an aberrant growth‐regulatory phenotype in colorectal carcinomas. The authors postulated that a similar mechanism occurred during the malignant evolution of small bowel carcinoid tumors. METHODS Mutational analysis of two coding regions in the TGFβRII gene associated with MSI and BAT‐26 within intron 5 of the mismatch repair gene, hMSH2, was undertaken in small bowel carcinoids (n = 14), lymph node metasasis (n = 1) and liver metastases (n = 5). Quantitative PCR analysis [TAQMAN, Applied Biosystems, Foster City, CA] was then undertaken to examine gene alterations in mismatch repair genes (hMLH1 and hMSH2) in small bowel carcinoids (n = 7) and matched normal mucosa (n = 5). Staining was then analyzed using quantitative tissue array profiling (AQUA analysis) in a small bowel EC carcinoid tissue microarray (n = 55 tumors) with immunostaining against TGFβRII and MSH2. RESULTS Mutational examination of the TFGβRII gene and BAT‐26 demonstrated that MSI was not present in any carcinoid material. Q RT‐PCR analysis demonstrated statistically significant increased message levels of hMSH2 but not hMLH1 in carcinoid tumors. Quantitative analysis of membrane TGFβRII immunostaining using AQUA demonstrated that TGFβRII expression was down‐regulated (P < 0.0002) in thirty‐three primary small bowel carcinoids that exhibited lymph node and liver metastases compared to normal mucosa. AQUA analysis of nuclear MSH2 immunostaining demonstrated no differences for MSH2 between normal tissue and carcinoid tumor metastasis. Small bowel carcinoids characterized by variable expression of TGFβRII, did not exhibit MSI and had no differences in MSH2 expression. CONCLUSIONS The molecular events leading to the formation of carcinoid tumors in the small bowel were different from those resulting in epithelial carcinomas. The usually slow‐growing and relatively nonaggressive carcinoid tumors had variable expression of TGFβRII but were associated with the retention of mismatch repair protein function and a microsatellite‐stable phenotype. Cancer 2005. © 2004 American Cancer Society.

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The clinicopathological features of gastric carcinomas with micro-satellite instability may be mediated by mutations of different ‘target genes’. A study of the TGFβRII, IGFII R and BAX genes

Cited by 47 publications

References 0 publications

Differences in genomic instability between intestinal- and diffuse-type gastric cancer

Differences in genomic instability between intestinal- and diffuse-type gastric cancer

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

Microsatellite instability and gene mutations in transforming growth factor‐beta type II receptor are absent in small bowel carcinoid tumors

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