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Neurofibromatosis and early onset of cancers in hMLH1-deficient children

Q Wang1, C Lasset, F Desseigne

  • 1Unité d'Oncologie Moléculaire, Institut National de la Santé et de la Recherche Médicale, Centre Léon Bérard, Lyon, France.

Cancer Research
|February 2, 1999
PubMed

Insights

This study identifies the first human compounds with homozygous inactivation of DNA mismatch repair (MMR) genes. MMR deficiency in children can cause neurofibromatosis type I and early cancers, suggesting MMR genes are crucial for preventing mutations.

Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Hereditary nonpolyposis colon cancer (HNPCC) is linked to DNA mismatch repair (MMR) gene mutations.
  • Germ-line mutations in MMR genes like hMLH1 and hMSH2 are primary causes of HNPCC.
  • Homozygous inactivation of MMR genes in humans has not been previously reported.

Purpose of the Study:

  • To report the first identification of human individuals with homozygous inactivation of a DNA mismatch repair (MMR) gene.
  • To investigate the clinical consequences of MMR deficiency during human development.
  • To explore the potential link between MMR deficiency and neurofibromatosis type I.

Main Methods:

  • Analysis of a hereditary nonpolyposis colon cancer family.
  • Clinical evaluation of MMR-deficient children from consanguineous matings.
  • Genetic analysis of DNA mismatch repair gene mutations.

Main Results:

  • Identified human compounds with homozygous inactivation of a MMR gene (hMLH1).
  • MMR-deficient children presented with de novo neurofibromatosis type I and early-onset extracolonic cancers.
  • Clinical features suggest MMR deficiency is compatible with development but can induce mutations.

Conclusions:

  • Homozygous inactivation of MMR genes is compatible with human development.
  • MMR deficiency may lead to increased mutation rates during embryogenesis.
  • The neurofibromatosis type 1 gene is a potential preferential target for mutations in MMR-deficient individuals.

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