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Identification of a novel germ-line mutation in the TP53 gene in a Mexican family with Li-Fraumeni syndrome.

Taja-Chayeb L, Vidal-Millán S, Gutiérrez-Hernández O, Trejo-Becerril C, Pérez-Cárdenas E, Chávez-Blanco A, de la Cruz-Hernández E, Dueñas-González A - World J Surg Oncol (2009)

Bottom Line: Germ-line mutations of the TP53 gene are known to cause Li-Fraumeni syndrome, an autosomal, dominantly inherited, high-penetrance cancer-predisposition syndrome characterized by the occurrence of a variety of cancers, mainly soft tissue sarcomas, adrenocortical carcinoma, leukemia, breast cancer, and brain tumors.The mutation comprises an insertion/duplication of seven nucleotides affecting codon 110 and generating a new nucleotide sequence and a premature stop codon at position 150.With this mutation, the p53 protein that should be translated lacks the majority of the DNA binding domain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Instituto Nacional de Cancerología (INCan), Mexico City, México. ltaja_chayeb@yahoo.com

ABSTRACT

Background: Germ-line mutations of the TP53 gene are known to cause Li-Fraumeni syndrome, an autosomal, dominantly inherited, high-penetrance cancer-predisposition syndrome characterized by the occurrence of a variety of cancers, mainly soft tissue sarcomas, adrenocortical carcinoma, leukemia, breast cancer, and brain tumors.

Methods: Mutation analysis was based on Denaturing high performance liquid chromatography (DHPLC) screening of exons 2-11 of the TP53 gene, sequencing, and cloning of DNA obtained from peripheral blood lymphocytes.

Results: We report herein on Li Fraumeni syndrome in a family whose members are carriers of a novel TP53 gene mutation at exon 4. The mutation comprises an insertion/duplication of seven nucleotides affecting codon 110 and generating a new nucleotide sequence and a premature stop codon at position 150. With this mutation, the p53 protein that should be translated lacks the majority of the DNA binding domain.

Conclusion: To our knowledge, this specific alteration has not been reported previously, but we believe it is the cause of the Li-Fraumeni syndrome in this family.

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DNA sequence showing the insertion and cDNA sequence generated by the mutation. A. Sequence analysis of TP53 exon 4 for the index patient. Bold underlined indicates the duplicated sequence, below which the wild-type sequence is shown. B. Changes in the cDNA sequence: new cDNA sequence (bold) and generation of a premature stop codon (italics). The 7 nucleotide insertion is underlined.
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Figure 3: DNA sequence showing the insertion and cDNA sequence generated by the mutation. A. Sequence analysis of TP53 exon 4 for the index patient. Bold underlined indicates the duplicated sequence, below which the wild-type sequence is shown. B. Changes in the cDNA sequence: new cDNA sequence (bold) and generation of a premature stop codon (italics). The 7 nucleotide insertion is underlined.

Mentions: Based on clinical data, the family was diagnosed with LFS. The pedigree (Figure 1) suggested that individual II-5 might be the carrier of the de novo TP53 mutation because none of his ancestors had had cancer. The first family member studied was the index patient. We analyzed exons 2-11 by DHPLC and observed an abnormal chromatogram in exon 4 (Figure 2). Subsequent direct sequencing of the aberrant PCR product of exon 4 demonstrated a 7-nucleotide insertion. Further analysis of the sequence demonstrated that the insertion was, in fact, tandem duplication (c.329-330insGTTTCCG). This duplication generates a frameshift and a premature stop signal at codon 150 (Figure 3).


Identification of a novel germ-line mutation in the TP53 gene in a Mexican family with Li-Fraumeni syndrome.

Taja-Chayeb L, Vidal-Millán S, Gutiérrez-Hernández O, Trejo-Becerril C, Pérez-Cárdenas E, Chávez-Blanco A, de la Cruz-Hernández E, Dueñas-González A - World J Surg Oncol (2009)

DNA sequence showing the insertion and cDNA sequence generated by the mutation. A. Sequence analysis of TP53 exon 4 for the index patient. Bold underlined indicates the duplicated sequence, below which the wild-type sequence is shown. B. Changes in the cDNA sequence: new cDNA sequence (bold) and generation of a premature stop codon (italics). The 7 nucleotide insertion is underlined.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806269&req=5

Figure 3: DNA sequence showing the insertion and cDNA sequence generated by the mutation. A. Sequence analysis of TP53 exon 4 for the index patient. Bold underlined indicates the duplicated sequence, below which the wild-type sequence is shown. B. Changes in the cDNA sequence: new cDNA sequence (bold) and generation of a premature stop codon (italics). The 7 nucleotide insertion is underlined.
Mentions: Based on clinical data, the family was diagnosed with LFS. The pedigree (Figure 1) suggested that individual II-5 might be the carrier of the de novo TP53 mutation because none of his ancestors had had cancer. The first family member studied was the index patient. We analyzed exons 2-11 by DHPLC and observed an abnormal chromatogram in exon 4 (Figure 2). Subsequent direct sequencing of the aberrant PCR product of exon 4 demonstrated a 7-nucleotide insertion. Further analysis of the sequence demonstrated that the insertion was, in fact, tandem duplication (c.329-330insGTTTCCG). This duplication generates a frameshift and a premature stop signal at codon 150 (Figure 3).

Bottom Line: Germ-line mutations of the TP53 gene are known to cause Li-Fraumeni syndrome, an autosomal, dominantly inherited, high-penetrance cancer-predisposition syndrome characterized by the occurrence of a variety of cancers, mainly soft tissue sarcomas, adrenocortical carcinoma, leukemia, breast cancer, and brain tumors.The mutation comprises an insertion/duplication of seven nucleotides affecting codon 110 and generating a new nucleotide sequence and a premature stop codon at position 150.With this mutation, the p53 protein that should be translated lacks the majority of the DNA binding domain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Instituto Nacional de Cancerología (INCan), Mexico City, México. ltaja_chayeb@yahoo.com

ABSTRACT

Background: Germ-line mutations of the TP53 gene are known to cause Li-Fraumeni syndrome, an autosomal, dominantly inherited, high-penetrance cancer-predisposition syndrome characterized by the occurrence of a variety of cancers, mainly soft tissue sarcomas, adrenocortical carcinoma, leukemia, breast cancer, and brain tumors.

Methods: Mutation analysis was based on Denaturing high performance liquid chromatography (DHPLC) screening of exons 2-11 of the TP53 gene, sequencing, and cloning of DNA obtained from peripheral blood lymphocytes.

Results: We report herein on Li Fraumeni syndrome in a family whose members are carriers of a novel TP53 gene mutation at exon 4. The mutation comprises an insertion/duplication of seven nucleotides affecting codon 110 and generating a new nucleotide sequence and a premature stop codon at position 150. With this mutation, the p53 protein that should be translated lacks the majority of the DNA binding domain.

Conclusion: To our knowledge, this specific alteration has not been reported previously, but we believe it is the cause of the Li-Fraumeni syndrome in this family.

Show MeSH
Related in: MedlinePlus