High Frequency of Germline p53 Mutations in Childhood Adrenocortical Cancer

Wagner, Josephine; Portwine, Carol; Rabin, Karen R.; LeClerc, J E; Narod, Steven A.; Malkin, David

doi:10.1093/jnci/86.22.1707

Cited by 205 publications

(120 citation statements)

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“…Adrenocortical carcinoma, an extremely rare tumor of childhood except in the setting of Beckwith-Wiedemann syndrome or LFS, has been associated with the p53 carrier state in 3/6 children studied (42). None of these individuals had a family history of cancer.…”

Section: Discussionmentioning

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

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Section: Discussionmentioning

confidence: 99%

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

Diller¹,

Sexsmith²,

Gottlieb³

et al. 1995

J. Clin. Invest.

190

121

View full text Add to dashboard Cite

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“…Over half of all families conforming to the de®nition of classic LFS and approximately one quarter of those which are Li ± Fraumeni-like (LFL, Birch et al, 1994) carry germline mutations to the TP53 gene (Malkin et al, 1990;Birch et al, 1994;Frebourg et al, 1995;Varley et al, 1997). Furthermore, a signi®cant proportion of patients with tumours which are typical of those seen in Li ± Fraumeni syndrome have also been shown to carry TP53 germline mutations at an increased frequency Sameshima et al, 1992;Toguchida et al, 1992;Brugieres et al, 1993;Kyritsis et al, 1994;McIntyre et al, 1994;Wagner et al, 1994;Chen et al, 1995;Diller et al, 1995;Li et al, 1995). TP53 is considered to be a tumour suppressor gene (Hollstein et al, 1991;Levine et al, 1991;Lane, 1992), and as such some tumours from patients with germline TP53 mutations have been analysed for loss of heterozygosity (LOH).…”

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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“…Virilizing features are seen in approximately 90% of pediatric patients with adrenocortical carcinoma, whereas, Cushing syndrome or nonfunctional tumors are the most common tumor type seen in adolescents and young adults at the time of diagnosis. Moreover, constitutional TP53 gene mutations are frequently involved in pediatric patients, but are relatively rare in adults [23]. The frequency of adrenocortical carcinoma is 0.4 per million during the first 4 years of life, and it decreases to 0.1 per million during the subsequent 10 years.…”

Section: Discussionmentioning

confidence: 99%

Virilizing adrenocortical carcinoma in a child with Turner syndrome and somatic TP53 gene mutation

Lee

Hong

et al. 2009

Eur J Pediatr

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Virilizing adrenocortical carcinoma and Turner syndrome have opposite clinical manifestations in some aspects. Here, we report on the first case of virilizing adrenocortical carcinoma in a girl with Turner syndrome. A 2 10/12-year-old girl presented pubic hair of Tanner stage III with clitomegaly, deepening of her voice, and tall stature. No other morphologic anomaly was found. Biochemical assessment revealed normal electrolytes with pronounced elevation of adrenal androgens. She was found to have a large mass of the left adrenal gland on abdominal computed tomography scan. She underwent complete resection of the mass, and pathology was consistent with adrenocortical carcinoma. She was tested for TP53 gene mutation, and we found a de novo TP53 gene mutation (Val143Ala) as well as a 45,X karyotype.

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High Frequency of Germline p53 Mutations in Childhood Adrenocortical Cancer

Cited by 205 publications

References 0 publications

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

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

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

Virilizing adrenocortical carcinoma in a child with Turner syndrome and somatic TP53 gene mutation

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