Li-Fraumeni and Li-Fraumeni—like syndrome among children diagnosed with pediatric cancer in Southern Brazil

Authors

  • Juliana Giacomazzi BSc, MSc, PhD,

    Corresponding author
    1. Laboratorio de Medicina Genomica, Experimental Research Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
    2. Post-Graduate Program in Medicine, Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
    3. Genetics Department, UFRGS, Porto Alegre, Brazil
    • Corresponding author: Juliana Giacomazzi, BSc, MSc, PhD, Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre and Genetics Departament, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2350, 90035-903 Porto Alegre, RS, Brazil; Fax: (011) 55 51 3359 7661 jugiacomazzi@gmail.com

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  • Simone G. Selistre MD,

    1. Post-Graduate Program in Medicine, Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
    2. Pediatric Oncology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
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  • Cristina Rossi MD,

    1. Laboratorio de Medicina Genomica, Experimental Research Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
    2. School of Medicine, UFRGS, Porto Alegre, Brazil
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  • Barbara Alemar BSc, MSc,

    1. Laboratorio de Medicina Genomica, Experimental Research Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
    2. Post-Graduate Program in Genetics and Molecular Biology, UFRGS, Porto Alegre, Brazil
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  • Patricia Santos-Silva,

    1. Laboratorio de Medicina Genomica, Experimental Research Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
    2. Post-Graduate Program in Medicine, Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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  • Fernando S. Pereira,

    1. Laboratorio de Medicina Genomica, Experimental Research Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
    2. School of Medicine, UFRGS, Porto Alegre, Brazil
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  • Cristina B. Netto MD, PhD,

    1. Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
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  • Silvia L. Cossio PhD,

    1. Laboratorio de Medicina Genomica, Experimental Research Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
    2. Post-Graduate Program in Medicine, Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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  • Daniela E. Roth MD,

    1. Pediatric Oncology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
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  • Algemir L. Brunetto MD, PhD,

    1. Pediatric Oncology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
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  • Marcelo Zagonel-Oliveira BSc, MSc,

    1. Instituto Nacional de Genetica Medica Populacional (INaGeMP), UFRGS, Porto Alegre, Brazil
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  • Ghyslaine Martel-Planche,

    1. International Agency for Research on Cancer, Lyon, France
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  • Jose R. Goldim BSc, PhD,

    1. Bioethics Research Laboratory, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
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  • Pierre Hainaut BSc, PhD,

    1. International Prevention Research Institute, Lyon, France
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  • Suzi A. Camey PhD,

    1. Department of Statistics, Institute of Mathematics, UFRGS, Porto Alegre, Brazil
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  • Patricia Ashton-Prolla MD, PhD

    1. Laboratorio de Medicina Genomica, Experimental Research Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
    2. Post-Graduate Program in Medicine, Medical Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
    3. Genetics Department, UFRGS, Porto Alegre, Brazil
    4. Post-Graduate Program in Genetics and Molecular Biology, UFRGS, Porto Alegre, Brazil
    5. Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
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  • We thank Cláudio Galvão, Lauro Greggianin, Camila Matzenbacher Bittar, and Filippo Vairo for their collaboration with patient recruitment; Diego D'Avila Paskulin, Marcia da Silveira Graudenz, and Luise Meurer for laboratory support; and Lavinia Schuler-Faccini and INaGeMP for their help with geomapping.

Abstract

BACKGROUND

Pediatric cancers are a feature in patients with Li-Fraumeni syndrome and its variant Li-Fraumeni–like syndrome (LFS/LFL). To the best of the authors' knowledge, TP53 germline mutations are currently the only molecular defect known to be associated with this disease. Recently, a specific germline mutation in this gene, p.R337H, has been reported at a high prevalence in Brazil.

METHODS

The prevalence of LFS/LFL was investigated in children with cancer who were diagnosed with tumors on the LFS/LFL spectrum and in a small consecutive series of controls without cancer. The prevalence of the germline p.R337H mutation and of other germline TP53 mutations was investigated in a general group of children with cancer and exclusively in children fulfilling the clinical criteria for LFS/LFL, respectively.

RESULTS

Among the 65 children without cancer, 1.5% had a family history of LFL whereas of the 292 children with cancer, 25.3% had a family history of LFL (P < .001). Screening for the p.R337H mutation identified 11 carriers (3.7%), 9 of whom were diagnosed with adrenocortical carcinomas (ACC) and 2 of whom were diagnosed with choroid plexus carcinomas. One of the ACC probands was homozygous mutant. The Brazilian founder haplotype and loss of heterozygosity at the p.R337H locus were present in all carriers. In addition, direct sequencing of the entire TP53 coding region and gene rearrangement analysis of probands fulfilling the criteria for LFL (Eeles 2 criteria, Birch and/or Chompret criteria) and who were negative for the p.R337H mutation revealed a DNA-binding domain pathogenic mutation, p.G245S, in 1 child.

CONCLUSIONS

TP53 p.R337H testing should be offered to Brazilian children diagnosed with ACC and choroid plexus carcinoma. A significant percentage of children with cancer in southern Brazil fulfill the criteria for LFL and should be referred for genetic risk assessment. Cancer 2013;119:4341–4349. © 2013 American Cancer Society.

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