Biallelic Germline Mutations of Mismatch‐Repair Genes and Paediatric Malignancies

Katharina Wimmer, Medical University Innsbruck, Innsbruck, Austria
Julia Etzler, Medical University Vienna, Vienna, Austria

Published online: September 2009

DOI: 10.1002/9780470015902.a0021484

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

Figure 1. Differences in primary tumour spectrum between carriers of biallelic MLH1/MSH2 and MSH6/PMS2 mutations, respectively; m.a.=median age.
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    Felton KE, Gilchrist DM and Andrew SE (2007) Constitutive deficiency in DNA mismatch repair. Clinical Genetics 71: 483–498.
    Magnusson S, Borg A, Kristoffersson U et al. (2008) Higher occurrence of childhood cancer in families with germline mutations in BRCA2, MMR and CDKN2A genes. Familial Cancer. 7: 331–337.
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    Ostergaard JR, Sunde L and Okkels H (2005) Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6. American Journal of Medical Genetics. Part A 139: 96–105, discussion 96.
    Poley JW, Wagner A, Hoogmans MM et al. (2007) Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple paediatric malignancies. Cancer 109: 2349–2356.
    Rahman N and Scott RH (2007) Cancer genes associated with phenotypes in monoallelic and biallelic mutation carriers: new lessons from old players. Human Molecular Genetics 16(Spec No 1): R60–R66.

Related Sub-Topics:

Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Cancer Genetics | Genomic Disorders | DNA Damage and Repair
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Article Title: Biallelic Germline Mutations of Mismatch‐Repair Genes and Paediatric Malignancies
 
How to Cite close
Wimmer, Katharina, and Etzler, Julia(Sep 2009) Biallelic Germline Mutations of Mismatch‐Repair Genes and Paediatric Malignancies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021484]