Immunotherapy holds the key to cancer treatment and prevention in constitutional mismatch repair deficiency (CMMRD) syndrome

Cancer Lett. 2017 Sep 10:403:159-164. doi: 10.1016/j.canlet.2017.06.018. Epub 2017 Jun 20.


Monoallelic germline mutations in one of the DNA mismatch repair (MMR) genes cause Lynch syndrome, with a high lifetime risks of colorectal and endometrial cancer at adult age. Less well known, is the constitutional mismatch repair deficiency (CMMRD) syndrome caused by biallelic germline mutations in MMR genes. This syndrome is characterized by the development of childhood cancer. Patients with CMMRD are at extremely high risk of developing multiple cancers including hematological, brain and intestinal tumors. Mutations in MMR genes impair DNA repair and therefore most tumors of patients with CMMRD are hypermutated. These mutations lead to changes in the translational reading frame, which consequently result in neoantigen formation. Neoantigens are recognized as foreign by the immune system and can induce specific immune responses. The growing evidence on the clinical efficacy of immunotherapies, such as immune checkpoint inhibitors, offers the prospect for treatment of patients with CMMRD. Combining neoantigen-based vaccination strategies and immune checkpoint inhibitors could be an effective way to conquer CMMRD-related tumors. Neoantigen-based vaccines might also be a preventive treatment option in healthy biallelic MMR mutation carriers. Future studies need to reveal the safety and efficacy of immunotherapies for patients with CMMRD.

Keywords: CMMRD; Cancer immunotherapy; Constitutional mismatch repair deficiency syndrome; Neoantigens; Prevention.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / adverse effects
  • Antibodies / therapeutic use*
  • Antigens, Neoplasm* / genetics
  • Antigens, Neoplasm* / immunology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / immunology
  • Brain Neoplasms / mortality
  • Brain Neoplasms / therapy*
  • Cancer Vaccines / adverse effects
  • Cancer Vaccines / therapeutic use*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / therapy*
  • DNA Mismatch Repair* / genetics
  • DNA Mismatch Repair* / immunology
  • DNA Repair Enzymes* / genetics
  • DNA Repair Enzymes* / immunology
  • Genetic Predisposition to Disease
  • Humans
  • Immunotherapy / adverse effects
  • Immunotherapy / methods*
  • Immunotherapy / mortality
  • Mutation*
  • Neoplastic Syndromes, Hereditary / genetics
  • Neoplastic Syndromes, Hereditary / immunology
  • Neoplastic Syndromes, Hereditary / mortality
  • Neoplastic Syndromes, Hereditary / therapy*
  • Phenotype


  • Antibodies
  • Antigens, Neoplasm
  • Cancer Vaccines
  • DNA Repair Enzymes

Supplementary concepts

  • Turcot syndrome