Constitutional mismatch repair-deficiency: current problems and emerging therapeutic strategies

Malak Abedalthagafi _

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Oncotarget. 2018; 9:35458-35469. https://doi.org/10.18632/oncotarget.26249

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Malak Abedalthagafi1,2

1Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia

2Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Correspondence to:

Malak Abedalthagafi, email: [email protected]

Keywords: CMMRD; childhood cancer; mismatch repair; immunotherapy; predisposition syndrome

Received: June 21, 2018     Accepted: October 08, 2018     Published: October 23, 2018


Mismatch repair (MMR) proteins remove errors from newly synthesized DNA, improving the fidelity of DNA replication. A loss of MMR causes a mutated phenotype leading to a predisposition to cancer.

In the last 20 years, an increasing number of patients have been described with biallelic MMR gene mutations in which MMR defects are inherited from both parents. This leads to a syndrome with recessive inheritance, referred to as constitutional mismatch repair-deficiency (CMMRD). CMMRD is a rare childhood cancer predisposition syndrome. The spectrum of CMMRD tumours is broad and CMMRD-patients possess a high risk of multiple cancers including hematological, brain and intestinal tumors. The severity of CMMRD is highlighted by the fact that patients do not survive until later life, emphasising the requirement for new therapeutic interventions.

Many tumors in CMMRD-patients are hypermutated leading to the production of truncated protein products termed neoantigens. Neoantigens are recognized as foreign by the immune system and induce antitumor immune responses. There is growing evidence to support the clinical efficacy of neoantigen based vaccines and immune checkpoint inhibitors (collectively referred to as immunotherapy) for the treatment of CMMRD cancers. In this review, we discuss the current knowledge of CMMRD, the advances in its diagnosis, and the emerging therapeutic strategies for CMMRD-cancers.

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