Identification of a germ-line mutation in the p53 gene in a patient with an intracranial ependymoma.

Metzger, Andrew; Sheffield, Val C.; Duyk, Geoffrey M.; Daneshvar, Laleh; Edwards, Michael S. B.; Cogen, Philip H.

doi:10.1073/pnas.88.17.7825

Cited by 103 publications

(45 citation statements)

References 27 publications

(44 reference statements)

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“…However, it soon became apparent that not all LFS families carried such mutations. Furthermore, mutations were identi®ed in certain families not meeting the LFS criteria and in unselected groups of patients with LFS component cancers (SantibanezKoref et al, 1991;Metzger et al, 1991;Sameshima et al, 1992;Wagner et al, 1994;Diller et al, 1995;Chen et al, 1995;Toguchida et al, 1992;Borresen et al, 1992;McIntyre et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Cancer phenotype correlates with constitutional TP53 genotype in families with the Li–Fraumeni syndrome

et al. 1998

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The Li ± Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li ± Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed signi®cantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a signi®cantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.

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Section: Introductionmentioning

confidence: 99%

Cancer phenotype correlates with constitutional TP53 genotype in families with the Li–Fraumeni syndrome

et al. 1998

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“…To our knowledge 39 tumours from patients with germline mutations at TP53 have been studied for LOH, with LOH detected in 69% of those tumours (Malkin et al, 1990;Chung et al, 1991;Metzger et al, 1991;Bùrresen et al, 1992;Felix et al, 1992Felix et al, , 1993Felix et al, , 1995Iavarone et al, 1992;Kovar et al, 1992;Prosser et al, 1992;Sameshima et al, 1992;Srivastava et al, 1992;Warneford et al, 1992;Eeles et al, 1993;Scott et al, 1993;Grayson et al, 1994;Gutierrez et al, 1994;Hamelin et al, 1994;Horio et al, 1994;Jolly et al, 1994;Plummer et al, 1994;Chen et al, 1995;Li et al, 1995;Lubbe et al, 1995). However, there has been no systematic study of LOH in a large series of patients with de®ned TP53 mutations, and in tumour material which has been characterised according to standard criteria by one pathologist.…”

Section: Introductionmentioning

confidence: 99%

A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li – Fraumeni patients carrying a mutation to the TP53 gene

et al. 1997

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We have studied a total of 36 tumours from 28 patients with germline mutations to the TP53 gene for loss of heterozygosity at TP53 using techniques of both direct sequencing and restriction fragment length polymorphism analysis. All patients were from families conforming to the de®nition of classical Li ± Fraumeni syndrome (LFS) or were Li ± Fraumeni-like (LFL). The data we have obtained show that loss of the wild-type TP53 gene is observed in under half (44%) of all tumours, and that the pattern of LOH at TP53 may be mutation speci®c. LOH has been observed in premalignant as well as invasive tumours. Two tumours (6%) show loss of the mutant allele and retention of the wild-type. To con®rm that TP53 is indeed the target for LOH events on chromosome 17, we have used additional microsatellite repeats to examine patterns of allelic imbalance along the length of chromosome 17. Data from this analysis indicate that TP53 is the target of loss, but reveal some other interesting patterns of allelic imbalance at other loci on chromosome 17.

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“…The relationship between LFS and constitutional p53 mutations is complex. Although the majority of LFS families analyzed to date harbor germline p53 mutations in the coding region of the gene ( 15,16,21,22), some LFS families lack detectable mutations (23,24), and constitutional mutations have been identified in some cancer patients without a family history of malignancy (25)(26)(27)(28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma.

Diller¹,

Sexsmith²,

Gottlieb³

et al. 1995

J. Clin. Invest.

190

121

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We investigated the possibility that a proportion of children with sporadic rhabdomyosarcoma (RMS) carry constitutional mutations of the p53 tumor suppressor gene. 33 patients with sporadic RMS at two large outpatient pediatric oncology clinics submitted blood samples. Genomic DNA was extracted from peripheral blood leukocytes and PCR was used to amplify exons 2-11 of the p53 gene. Amplified genomic DNA was screened for the presence of germline p53 mutations using single-strand conformation polymorphism (SSCP) analysis. The DNA sequence of those samples that showed aberrant migration of bands on SSCP analysis was determined to identify the precise nature of the gene mutations. Patient records were reviewed to assess clinical correlates of the mutant p53 carrier state. Heterozygous constitutional mutations were detected in 3/33 patient samples screened. Two of these missense mutations are located in exon 7 and one in exon 8 of the p53 gene. The presence of mutations was not correlated with tumor histology, stage, or site. However, an association between young age at diagnosis and presence of a constitutional p53 mutation was noted: 3/13 children under the age of 3 yr at diagnosis carried mutations, whereas none of 20 children over 3 yr of age at diagnosis harbored a detectable constitutional mutation. These results in children with RMS corroborates previous findings in other clinical settings suggesting that the mutant p53 carrier state may predispose individuals to malignancy at an early age. Although this study did not assess whether the mutations were preexisting or new germline alterations, assessment of close relatives of RMS patients for cancer risk and predictive genetic testing may be indicated. (J. Clin. Invest. 1995Invest. . 95:1606Invest. -1611

show abstract

Identification of a germ-line mutation in the p53 gene in a patient with an intracranial ependymoma.

Cited by 103 publications

References 27 publications

Cancer phenotype correlates with constitutional TP53 genotype in families with the Li–Fraumeni syndrome

Cancer phenotype correlates with constitutional TP53 genotype in families with the Li–Fraumeni syndrome

A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li – Fraumeni patients carrying a mutation to the TP53 gene

Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma.

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