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Biallelic Germline Mutations of Mismatch-Repair Genes and Paediatric Malignancies

  1. Katharina Wimmer2,
  2. Julia Etzler1

Published Online: 15 SEP 2009

DOI: 10.1002/9780470015902.a0021484

eLS

eLS

How to Cite

Wimmer, K. and Etzler, J. 2009. Biallelic Germline Mutations of Mismatch-Repair Genes and Paediatric Malignancies. eLS. .

Author Information

  1. 1

    Medical University Vienna, Vienna, Austria

  2. 2

    Medical University Innsbruck, Innsbruck, Austria

Publication History

  1. Published Online: 15 SEP 2009

Abstract

Constitutional impairment of the human deoxyribonucleic acid (DNA) mismatch repair (MMR) system due to biallelic germline mutations in one of the MMR genes MLH1, MSH2, MSH6 or PMS2 causes a condition that may best be described as constitutional MMR-deficiency (CMMR-D) syndrome. Clinically, the syndrome is characterized by a strong predisposition to various paediatric malignancies, primarily haematological malignancies, brain tumours and early onset colorectal cancer as well as signs reminiscent of neurofibromatosis type 1 (NF1). This phenotypic overlap of CMMR-D syndrome and NF1 may hamper or delay proper diagnosis of the underlying genetic condition, thus bearing a challenge for clinicians and geneticists alike. The article briefly reports the clinical findings in the so far described CMMR-D syndrome patients and points out possible phenotype–genotype correlations with respect to tumour spectrum and age of malignancy onset.

Key concepts

  • The DNA MMR system is responsible for the correction of single base pair mismatches and small misalignments that continuously arise during DNA replication.

  • Defective MMR will lead to the accumulation of uncorrected mismatches in the genome and may ultimately result in cancer development.

  • In humans, biallelic germline mutations in one of the MMR genes MLH1, MSH2, MSH6 and PMS2 cause a strong predisposition to paediatric malignancies.

  • The condition may best be termed CMMR-D syndrome.

  • Children affected by CMMR-D syndrome primarily develop haematological malignancies, brain tumours and early onset colorectal cancers as well as café-au-lait spots (CLS) and other signs reminiscent of neurofibromatosis type 1.

  • The phenotypic overlap of CMMR-D syndrome and neurofibromatosis type 1 (NF1), one of the most common autosomal dominant genetic disorders, might hamper or delay proper diagnosis of the condition.

  • There are indications that CMMR-D syndrome patients carrying biallelic MLH1/MSH2 and MSH6/PMS2 mutations, respectively, might differ in tumour types and age of malignancy onset.

  • Microsatellite instability testing and/or immunohistochemical expression analysis for the MMR genes as well as reliable mutation analysis of MLH1, MSH2, MSH6 and PMS2 is important not only for proper diagnosis of CMMR-D syndrome patients but also has implications for their relatives, as heterozygous germline mutations in these MMR genes are known to cause hereditary nonpolyposis colorectal cancer (HNPCC).

Keywords:

  • mismatch repair (MMR);
  • hereditary cancer;
  • childhood cancer syndrome;
  • HNPCC;
  • NF1