Mutation frequencies at codon 248 of the p53 tumour suppressor gene are not increased in colon cancer cell lines with the RER+ phenotype

Mancuso, Tommaso; Aguilar, Fernando; Pescarolo, Maria Pia; Clerico, Luana; Russo, Patrizia; Parodi, Silvio

doi:10.1093/nar/25.18.3643

Cited by 13 publications

(6 citation statements)

References 35 publications

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“…We found concordance of p53 mutations and mismatch repair gene mutations in eight cases of secondary tumors. This is contrary to other studies showing that in tumors of the intestinal type, which had a germline mutation in an hMSH2 or hMLH1 gene, frequencies of mutation in adenomatous polyposis coli, p53, K‐ ras ‐2 genes, and LOH on tumor suppressor regions were extremely low 52–59. Moreover, the lack of instability or very rare microsatellite instability (1 of 54 samples) has been documented in primary pediatric brain tumors 31, 60.…”

Section: Discussioncontrasting

confidence: 67%

Microsatellite instability and p53 mutations in pediatric secondary malignant neoplasms

Gafanovich

Ramu

Krichevsky

et al. 1999

Cancer

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BACKGROUND The past decade has witnessed a growing frequency of therapy‐related secondary tumors. The authors studied nine children with secondary malignancies. The primary tumors were bilateral retinoblastoma, neuroblastoma, brain tumor, Wilms' tumor, colon adenocarcinoma, and Hodgkin's disease. The secondary tumors were osteosarcoma at the site of previous radiotherapy, myelodysplastic syndrome, acute myelocytic leukemia, glioblastoma, thyroid carcinoma, and B‐cell lymphoma. METHODS DNA was extracted from the primary and secondary tumors and analyzed for genetic alterations in the p53 gene and in 7 separate microsatellites. RESULTS The authors found p53 mutations in 7 patients, loss of heterozygosity in 1 patient, and both mutation and loss of heterozygosity in 1 patient. Mutations were demonstrated in the primary tumors only in two patients and in the secondary tumors only in three patients. Two patients had a mutation in both the primary and the secondary tumor; in both patients the two mutations were in different exons. Microsatellite instability (MIN) was identified in five to seven loci in the secondary tumors of all patients. CONCLUSIONS The observed MIN is compatible with the presence of a mutator phenotype that predisposes these children to the development of secondary malignancies. Cancer 1999;85:504–10. © 1999 American Cancer Society.

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Section: Discussioncontrasting

confidence: 67%

Microsatellite instability and p53 mutations in pediatric secondary malignant neoplasms

Gafanovich

Ramu

Krichevsky

et al. 1999

Cancer

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“…We identified a mutation affecting amino acid 246 (R246H), which is considered equivalent to amino acid 248 in human p53, a known mutational hot spot. 69 Of interest, the GLI1 -expressing medulloblastoma cell line, Daoy, also carries a p53 mutation (C242F). 68 Together, this suggests that at least sometimes, p53 mutations may shift the balance toward dysregulated cell survival in GLI1 -expressing medulloblastomas and that during development functional interactions between GLI1 and p53 may maintain normal cellular homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Defining a role for Sonic hedgehog pathway activation in desmoplastic medulloblastoma by identifying GLI1 target genes

Yoon

Gilbertson

Iannaccone

et al. 2008

Intl Journal of Cancer

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A subgroup of medulloblastomas shows constitutive activation of the Sonic hedgehog pathway with expression of GLI1. We identified the subset of GLI1 transforming target genes specifically expressed in medulloblastomas by comparing GLI1 targets in RK3E cells transformed by GLI1 with the gene expression profile of Sonic hedgehog signature medulloblastomas. We identified 1,823 genes whose expression was altered more than 2-fold in 2 independent RK3E + GLI1 cell lines. We identified 25 whose expression was altered similarly in medulloblastomas expressing GLI1. We identified potential GLI binding elements in the regulatory regions of 10 of these genes, confirmed that GLI1 binds the regulatory regions and activates transcription of select genes, and showed that GLI1 directly represses transcription of Krox-20. We identified upregulation of CXCR4, a chemokine receptor that plays roles in the proliferation and migration of granule cell neuron precursors during development, supporting the concept that reinitiation of developmental programs may contribute to medulloblastoma tumorigenesis. In addition, the targets suggest a pathway through which GLI1 may ultimately affect medulloblastoma cell proliferation, survival and genomic stability by converging on p53, SGK1, MGMT and NTRK2. We identify a p53 mutation in RK3E + GLI1 cells, suggesting that p53 mutations may sometimes shift the balance toward dysregulated tumor cell survival.

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“…However, well‐differentiated adenocarcinomas were significantly more likely to harbour a TP53 mutation than moderately or poorly differentiated carcinomas. Well‐differentiated carcinomas are associated with fewer genetic abnormalities than poorly differentiated carcinomas, 41 and it has also been shown that the presence of a TP53 mutation is inversely related to microsatellite instability and is associated with fewer other genetic abnormalities 35,42,43 . It is feasible that a TP53 mutation may result in neoplastic progression without the need for many other genetic insults, thereby resulting in the development of a well‐differentiated carcinoma.…”

Section: Discussionmentioning

confidence: 99%

TP53 mutations in malignant and premalignant Barrett’s esophagus

Dolan¹,

Walker²,

Gosney³

et al. 2003

Diseases of the Esophagus

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In order to improve the efficacy of endoscopic surveillance of Barrett's esophagus, markers of neoplastic progression in addition to dysplasia are required. The aim of the present study was to assess TP53 mutational analysis as a method of identifying patients with Barrett's esophagus who are at greatest risk of adenocarcinoma, for whom endoscopic surveillance is most appropriate. TP53 mutational analysis was initially performed on premalignant and malignant tissue from 30 patients undergoing esophagectomy for adenocarcinoma, and on premalignant biopsies from 48 patients participating in a Barrett's surveillance program. Surveillance patients were followed up endoscopically and histologically for a median of 5 years following TP53 assessment. Mutational analysis was performed by single-strand conformation polymorphism analysis and direct DNA sequencing. TP53 mutations were detected in 10 of 30 esophageal adenocarcinomas, and were more common in well-differentiated carcinomas. An identical TP53 mutation was detected in carcinoma and adjacent dysplasia. Two patients with premalignant Barrett's esophagus had TP53 mutations and one of these patients developed adenocarcinoma on follow up whilst the other has not yet progressed beyond metaplasia. No patient without TP53 mutation developed high-grade dysplasia or adenocarcinoma. TP53 mutations are detected in 33% of esophageal adenocarcinomas and in 4% of premalignant Barrett's esophagus in patients undergoing endoscopic surveillance. TP53 mutation can be detected before the development of high-grade dysplasia or carcinoma, and may be useful in stratifying the risk of adenocarcinoma in patients with Barrett's esophagus.

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Mutation frequencies at codon 248 of the p53 tumour suppressor gene are not increased in colon cancer cell lines with the RER+ phenotype

Cited by 13 publications

References 35 publications

Microsatellite instability and p53 mutations in pediatric secondary malignant neoplasms

Microsatellite instability and p53 mutations in pediatric secondary malignant neoplasms

Defining a role for Sonic hedgehog pathway activation in desmoplastic medulloblastoma by identifying GLI1 target genes

TP53 mutations in malignant and premalignant Barrett’s esophagus

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