Japanese Journal of Clinical Oncology 31:349-351 (2001)
© 2001 Foundation for Promotion of Cancer Research
Germline p53 Mutation in a Patient with Multiple Primary Cancers
1Biology and 3Pathology Divisions, National Cancer Center Research Institute, Tokyo, 4Orthopedic Division, National Cancer Center Hospital, Tokyo and 2Department of Orthopedic Surgery, Chiba University, Chiba, Japan
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ABSTRACT |
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 TOP ABSTRACT GENETICS SUMMARYCASE REPORT AND GENETIC...METHODS FOR MUTATION DETECTIONAcknowledgmentsREFERENCES |
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We report a case of multiple primary cancers having a germline missense mutation of the p53 gene. The patient was a Japanese female and had a history of five different types of cancers. PCR/direct sequencing analysis revealed the presence of a nucleotide substitution, AGC (Ser) to AGG (Arg), at codon 106 of the p53 gene in DNA from non-cancerous breast tissue. This is the first case of germline p53 mutation at codon 106, and could contribute to establishing correlations between the types and locations of germline p53 mutations and their phenotypical consequences.
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GENETICS SUMMARY |
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TOPABSTRACTGENETICS SUMMARYCASE REPORT AND GENETIC...METHODS FOR MUTATION DETECTIONAcknowledgmentsREFERENCES |
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Disorder: Multiple primary cancer
Ethnicity of patients: Japanese
Gene: TP53
GenBank accession number: U94788
Chromosomal assignment: 17p13.1
Type of DNA variant: A germline missense mutation
Mutation: AGC (Ser, wild-type) to AGG (Arg) substitution at codon 106 of the p53 gene
Allelic frequency: Not tested
Method of mutation detection: PCR/direct sequencing
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CASE REPORT AND GENETIC ANALYSIS |
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TOPABSTRACTGENETICS SUMMARYCASE REPORT AND GENETIC...METHODS FOR MUTATION DETECTIONAcknowledgmentsREFERENCES |
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Germline mutations of the p53 gene have been found in individuals with Li–Fraumeni syndrome (LFS) (1–8). LFS is a dominantly inherited disorder characterized by early-onset breast cancer, sarcoma and other cancers. The most widely used criteria of LFS are as follows: a proband with sarcoma prior to the age of 45 years; a first-degree relative with any cancer diagnosed by age 45 years; and another first- or second-degree relative with any cancer before age 45 years or a sarcoma at any age (3,4,8,9). Li–Fraumeni families often contain members with multiple primary cancers (10–15). Germline p53 mutations have also been detected in individuals with multiple primary cancers whose family histories did not conform to LFS (5,10–12,14). Here, we report that a case with multiple primary cancers had a germline missense mutation of the p53 gene.
The patient was a Japanese female and had a history of five different types of cancers (Fig. 1). She had suffered from osteosarcomas of the left and right femurs at the age of 9 and 25 years, respectively and Paget carcinomas in the left and right breasts at the age of 19 and 24 years, respectively. Furthermore, she was affected by lung adenocarcinoma at the age of 26 years. Finally, she died of lung metastases of osteosarcoma at the age of 28 years. Her father died of lung cancer at the age of 27 years and her grandmother died of gastric cancer at the age of 65 years.
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The history of multiple primary cancers and the early onset of lung cancer in her and her father prompted us to examine the status of the germline p53 gene. It was previously shown that the nucleotide substitution of AGC (Ser) to AGG (Arg) at codon 106 of the p53 gene was present in the osteosarcoma tissue of her right femur (16). However, it has not been determined whether such a substitution was a germline or a somatic mutation. Therefore, we examined the non-cancerous breast tissue obtained at surgery of Paget carcinoma. Genomic DNA was extracted from the paraffin-embedded tissue as described by Gruis et al. (17), with a slight modification. In summary, deparaffinized tissue was suspended in digestion buffer (200 mg/ml proteinase K in 100 mM Tris–HCl, 1 mM EDTA and 0.5% Tween 20) at 37°C for 24 h. After heat inactivation of proteinase K, the samples were centrifuged and the supernatants were used as PCR templates. PCR/direct sequencing analysis revealed that the nucleotide substitution at codon 106 was a germline missense mutation (Fig. 2).
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Four cases of somatic mutations to AGG (Arg) at codon 106 of the p53 gene have been deposited in the p53 mutation database (http://www.umd.necker.fr:2001/) and there are no cases of germline mutations at that codon reported (18). Up to now, only a limited number of germline p53 mutations have been reported in the world. Therefore, the collection of a larger set of data is necessary to establish correlations between the types and locations of germline p53 mutations and their phenotypical consequences. Information on such genotype–phenotype correlations may improve the counseling and preventative approaches undertaken to aid the affected families.
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METHODS FOR MUTATION DETECTION |
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TOPABSTRACTGENETICS SUMMARYCASE REPORT AND GENETIC...METHODS FOR MUTATION DETECTIONAcknowledgmentsREFERENCES |
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PCR/direct sequencing was performed with the following conditions and parameters:
PCR primer, forward: 5'GCC CCT GCA CCA GCA GC3'
PCR primer, reverse: 5'CCA GGC ATT GAA GTC TCA TG3'
Size of PCR product: 205 bp
Thermal cycle profile:
Initial denaturation: 95°C, 10 min
50 cycles of 95°C, 20 s/58°C, 30 s/72°C, 30 s
Final extension: 72°C,10 min
Sequencing primer: the same as the PCR primers
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Acknowledgments |
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TOPABSTRACTGENETICS SUMMARYCASE REPORT AND GENETIC...METHODS FOR MUTATION DETECTIONAcknowledgmentsREFERENCES |
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This work was supported in part by a Grant-in-Aid for the 2nd Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare, Japan. K. Kimura is the recipient of a research resident fellowship from the Foundation for Promotion of Cancer Research. We thank H. Moriya and T. Umeda for their encouragement throughout this study.
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FOOTNOTES |
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+ For reprints and all correspondence: Jun Yokota, Biology Division, National Cancer Center Research Institute, 1–1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
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REFERENCES |
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TOPABSTRACTGENETICS SUMMARYCASE REPORT AND GENETIC...METHODS FOR MUTATION DETECTIONAcknowledgmentsREFERENCES |
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Received February 9, 2001; accepted March 26, 2001.
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