Genetic and Clinical Determinants of Constitutional Mismatch Repair Deficiency Syndrome: Report From the Constitutional Mismatch Repair Deficiency Consortium

Eur J Cancer. 2014 Mar;50(5):987-96. doi: 10.1016/j.ejca.2013.12.005. Epub 2014 Jan 15.

Abstract

Background: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited.

Methods: We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented.

Results: Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive.

Discussion: CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.

Keywords: Constitutional mismatch repair deficiency syndrome; MLH1; MSH2; MSH6; Microsatellite instability; PMS2.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Adolescent
  • Cafe-au-Lait Spots / diagnosis
  • Cafe-au-Lait Spots / genetics
  • Cafe-au-Lait Spots / metabolism
  • Child
  • Child, Preschool
  • DNA Mismatch Repair / genetics*
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Family Health
  • Female
  • Humans
  • Immunohistochemistry
  • Infant
  • Male
  • Microsatellite Instability*
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / genetics
  • MutS Homolog 2 Protein / metabolism
  • Mutation*
  • Neoplasms / diagnosis
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Pedigree
  • Syndrome

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • Nuclear Proteins
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • MSH2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • DNA Repair Enzymes