Biallelic Germline Mutations of Mismatch‐Repair Genes and Paediatric Malignancies

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

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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References

Auclair J, Leroux D, Desseigne F et al. (2007) Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Human Mutation 28: 1084–1090.

Bougeard G, Charbonnier F, Moerman A et al. (2003) Early onset brain tumor and lymphoma in MSH2‐deficient children. American Journal of Human Genetics 72: 213–216.

Clendenning M, Hampel H, LaJeunesse J et al. (2006) Long‐range PCR facilitates the identification of PMS2‐specific mutations. Human Mutation 27: 490–495.

Etzler J, Peyrl A, Zatkova A et al. (2008) RNA‐based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference. Human Mutation 29: 299–305.

Hayward BE, De Vos M, Valleley EM et al. (2007) Extensive gene conversion at the PMS2 DNA mismatch repair locus. Human Mutation 28: 424–430.

Hamilton SR, Liu B, Parsons RE et al. (1995) The molecular basis of Turcot's syndrome. New England Journal of Medicine 332: 839–847.

Jiricny J (2006) The multifaceted mismatch‐repair system. Nature Reviews. Molecular Cell Biology 7: 335–346.

Kruger S, Kinzel M, Walldorf C et al. (2008) Homozygous PMS2 germline mutations in two families with early onset haematological malignancy, brain tumours, HNPCC‐associated tumours, and signs of neurofibromatosis type 1. European Journal of Human Genetics 16: 62–72.

Plaschke J, Engel C, Kruger S et al. (2004) Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. Journal of Clinical Oncology 22: 4486–4494.

Rahner N, Hoefler G, Hogenauer C et al. (2008) Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus. American Journal of Medical Genetics. Part A 146A: 1314–1319.

Ricciardone MD, Ozcelik T, Cevher B et al. (1999) Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Research 59: 290–293.

Scott RH, Mansour S, Pritchard‐Jones K et al. (2007) Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nature Clinical Practice. Oncology 4: 130–134.

Truninger K, Menigatti M, Luz J et al. (2005) Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 128: 1160–1171.

Wang Q, Lasset C, Desseigne F et al. (1999) Neurofibromatosis and early onset of cancers in hMLH1‐deficient children. Cancer Research 59: 294–297.

Wang Q, Montmain G, Ruano E et al. (2003) Neurofibromatosis type 1 gene as a mutational target in a mismatch repair‐deficient cell type. Human Genetics 112: 117–123.

Further Reading

Bandipalliam P (2005) Syndrome of early onset colon cancers, hematologic malignancies & features of neurofibromatosis in HNPCC families with homozygous mismatch repair gene mutations. Familial Cancer 4: 323–333.

De Vos M, Hayward BE, Charlton R et al. (2006) PMS2 mutations in childhood cancer. Journal of National Cancer Institute 98: 358–361.

De Vos M, Hayward BE, Picton S, Sheridan E and Bonthron DT (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. American Journal of Human Genetics 74: 954–964.

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.

Menko FH, Kaspers GL, Meijer GA et al. (2004) A homozygous MSH6 mutation in a child with cafe‐au‐lait spots, oligodendroglioma and rectal cancer. Familial Cancer 3: 123–127.

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.

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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]