An identical, complex TP53 mutation arising independently in two unrelated families with diverse cancer profiles

The complexity of interpreting cancer risk in carriers

E. M. Pinto, R. C. Ribeiro, J. Li, L. Taja-Chayeb, L. F. Carrasco, M. De Lourdes Peña-Torres, S. Vidal-Millán, H. Maldonado-Mtz, A. Dueñas-González, Lisa McGregor, G. P. Zambetti

Research output: Contribution to journalArticle

Abstract

Most inherited TP53 mutations have been identified in individuals with a family cancer predisposition syndrome, in which the activity of p53 mutants is severely reduced. However, germline p53 mutants in children with sporadic adrenocortical or choroid plexus tumors exhibit a wide range of functional activity. Here, we demonstrate the occurrence of a complex germline TP53 mutation in two unrelated families with different cancer phenotypes, neither fulfilling the classic criteria for Li-Fraumeni syndrome. The TP53 mutation consists of a duplication of 7 bp in exon 4, resulting in a frame shift and premature stop signal. Haplotype analysis indicated that the mutation arose independently in the two families. Analysis of the DNA secondary structure predicts the TP53 mutation occurred within a hairpin loop. Additional germline complex mutations occurring within the same region of exon 4 have been identified in the IARC database. Our findings suggest that certain TP53 regions are prone to intrinsic genetic alterations, possibly through defects in DNA replication or repair. Further, carriers of the same TP53 mutation can have diverse cancer profiles, illustrating the complexity of genetic counseling and risk prediction.

Original languageEnglish (US)
Article numbere1
JournalOncogenesis
Volume1
Issue number2
DOIs
StatePublished - Nov 13 2012

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Mutation
Germ-Line Mutation
Neoplasms
Exons
Choroid Plexus Neoplasms
Li-Fraumeni Syndrome
Genetic Counseling
DNA Replication
DNA Repair
Haplotypes
Databases
Phenotype
DNA

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

Pinto, E. M., Ribeiro, R. C., Li, J., Taja-Chayeb, L., Carrasco, L. F., De Lourdes Peña-Torres, M., ... Zambetti, G. P. (2012). An identical, complex TP53 mutation arising independently in two unrelated families with diverse cancer profiles: The complexity of interpreting cancer risk in carriers. Oncogenesis, 1(2), [e1]. https://doi.org/10.1038/oncsis.2012.1
Pinto, E. M. ; Ribeiro, R. C. ; Li, J. ; Taja-Chayeb, L. ; Carrasco, L. F. ; De Lourdes Peña-Torres, M. ; Vidal-Millán, S. ; Maldonado-Mtz, H. ; Dueñas-González, A. ; McGregor, Lisa ; Zambetti, G. P. / An identical, complex TP53 mutation arising independently in two unrelated families with diverse cancer profiles : The complexity of interpreting cancer risk in carriers. In: Oncogenesis. 2012 ; Vol. 1, No. 2.
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abstract = "Most inherited TP53 mutations have been identified in individuals with a family cancer predisposition syndrome, in which the activity of p53 mutants is severely reduced. However, germline p53 mutants in children with sporadic adrenocortical or choroid plexus tumors exhibit a wide range of functional activity. Here, we demonstrate the occurrence of a complex germline TP53 mutation in two unrelated families with different cancer phenotypes, neither fulfilling the classic criteria for Li-Fraumeni syndrome. The TP53 mutation consists of a duplication of 7 bp in exon 4, resulting in a frame shift and premature stop signal. Haplotype analysis indicated that the mutation arose independently in the two families. Analysis of the DNA secondary structure predicts the TP53 mutation occurred within a hairpin loop. Additional germline complex mutations occurring within the same region of exon 4 have been identified in the IARC database. Our findings suggest that certain TP53 regions are prone to intrinsic genetic alterations, possibly through defects in DNA replication or repair. Further, carriers of the same TP53 mutation can have diverse cancer profiles, illustrating the complexity of genetic counseling and risk prediction.",
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Pinto, EM, Ribeiro, RC, Li, J, Taja-Chayeb, L, Carrasco, LF, De Lourdes Peña-Torres, M, Vidal-Millán, S, Maldonado-Mtz, H, Dueñas-González, A, McGregor, L & Zambetti, GP 2012, 'An identical, complex TP53 mutation arising independently in two unrelated families with diverse cancer profiles: The complexity of interpreting cancer risk in carriers', Oncogenesis, vol. 1, no. 2, e1. https://doi.org/10.1038/oncsis.2012.1

An identical, complex TP53 mutation arising independently in two unrelated families with diverse cancer profiles : The complexity of interpreting cancer risk in carriers. / Pinto, E. M.; Ribeiro, R. C.; Li, J.; Taja-Chayeb, L.; Carrasco, L. F.; De Lourdes Peña-Torres, M.; Vidal-Millán, S.; Maldonado-Mtz, H.; Dueñas-González, A.; McGregor, Lisa; Zambetti, G. P.

In: Oncogenesis, Vol. 1, No. 2, e1, 13.11.2012.

Research output: Contribution to journalArticle

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T1 - An identical, complex TP53 mutation arising independently in two unrelated families with diverse cancer profiles

T2 - The complexity of interpreting cancer risk in carriers

AU - Pinto, E. M.

AU - Ribeiro, R. C.

AU - Li, J.

AU - Taja-Chayeb, L.

AU - Carrasco, L. F.

AU - De Lourdes Peña-Torres, M.

AU - Vidal-Millán, S.

AU - Maldonado-Mtz, H.

AU - Dueñas-González, A.

AU - McGregor, Lisa

AU - Zambetti, G. P.

PY - 2012/11/13

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N2 - Most inherited TP53 mutations have been identified in individuals with a family cancer predisposition syndrome, in which the activity of p53 mutants is severely reduced. However, germline p53 mutants in children with sporadic adrenocortical or choroid plexus tumors exhibit a wide range of functional activity. Here, we demonstrate the occurrence of a complex germline TP53 mutation in two unrelated families with different cancer phenotypes, neither fulfilling the classic criteria for Li-Fraumeni syndrome. The TP53 mutation consists of a duplication of 7 bp in exon 4, resulting in a frame shift and premature stop signal. Haplotype analysis indicated that the mutation arose independently in the two families. Analysis of the DNA secondary structure predicts the TP53 mutation occurred within a hairpin loop. Additional germline complex mutations occurring within the same region of exon 4 have been identified in the IARC database. Our findings suggest that certain TP53 regions are prone to intrinsic genetic alterations, possibly through defects in DNA replication or repair. Further, carriers of the same TP53 mutation can have diverse cancer profiles, illustrating the complexity of genetic counseling and risk prediction.

AB - Most inherited TP53 mutations have been identified in individuals with a family cancer predisposition syndrome, in which the activity of p53 mutants is severely reduced. However, germline p53 mutants in children with sporadic adrenocortical or choroid plexus tumors exhibit a wide range of functional activity. Here, we demonstrate the occurrence of a complex germline TP53 mutation in two unrelated families with different cancer phenotypes, neither fulfilling the classic criteria for Li-Fraumeni syndrome. The TP53 mutation consists of a duplication of 7 bp in exon 4, resulting in a frame shift and premature stop signal. Haplotype analysis indicated that the mutation arose independently in the two families. Analysis of the DNA secondary structure predicts the TP53 mutation occurred within a hairpin loop. Additional germline complex mutations occurring within the same region of exon 4 have been identified in the IARC database. Our findings suggest that certain TP53 regions are prone to intrinsic genetic alterations, possibly through defects in DNA replication or repair. Further, carriers of the same TP53 mutation can have diverse cancer profiles, illustrating the complexity of genetic counseling and risk prediction.

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