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

Abstract

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.

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

Figure 1

(A) Schematic of MMR in a healthy cell (adapted from [12]). The proofreading capability of the DNA polymerases (POL) and the MMR system recognises and prevent errors (black circles) during DNA replication. (B) CMMRD. Inherited MMR defects (X) that lead to a loss of MMR function/expression lead to accumulated mutations and a predisposition to cancer during adulthood. When a combination of mutations affect POL and MMR function, the accumulation of mutations become more rapid and the onset of cancer occurs in young children (CMMRD).

Figure 2. CMMRD genetics

LS is an autosomal dominant disorder caused by defects in one of DNA MMR genes. Siblings of two parents with LS can develop CMMRD (biallelic MMR mutations). The spectrum of cancers observed for CMMRD are more severe than those found in LS. Up to 50% of children develop brain tumours, around 50% digestive tract cancers and approximately 33% develop haematological malignancies.