Research Questions

Detection of frameshift mutations and neoantigens in children with constitutional mismatch repair deficiency syndrome

One of the most aggressive forms of childhood cancer predisposition syndromes is constitutional mismatch repair deficiency syndrome (CMMRD). CMMRD results from biallelic deleterious germline mutations in one of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, or PMS2. Children with CMMRD develop hematological malignancies, brain tumors, gastrointestinal cancers, and other cancers. Compared to cancers associated with Lynch syndrome (LS) that is caused by heterozygous mutations in the MMR genes, CMMRD-associated cancers tend to occur at a younger age (in particular hematological malignancies and brain tumors) and are a broad-spectrum and more aggressive. CMMRD is a rare disease and thus has not been extensively investigated. Currently, there is no consensus on the criteria for the diagnostic evaluation of CMMRD. However, most researchers recommend testing for CMMRD for children with café au lait spots and either of consanguineous parents or family history of LS-spectrum cancers, hematological malignancies, or brain tumors. DNA MMR deficiency can trigger frameshift mutations in the coding microsatellites, which can give rise to frameshift peptide (FSP) neoantigens. A wide spectrum of FSP neoantigens and endogenous anti-FSP immune responses have been demonstrated in patients with LS. Although MSI testing has not been reliably used in the diagnosis of CMMRD tumors, especially hematological and CNS malignancies, a recent study has shown that germline MSI (gMSI) can be demonstrated in children with CMMRD. It is possible that children with CMMRD also harbor FSP neoantigens, which may drive tumorigenic process. To identify children with CMMRD in the childhood cancer cohort, children diagnosed with hematological malignancies or brain tumors with/without suspected CMMRD can be selected for tumor and germline molecular analysis, including the presence of MMR gene mutations, gMSI, and FSP neoantigens using tumor and peripheral blood mononuclear cell specimens.

How will your idea make a difference

In children with suspected CMMRD, plasma cfDNA and lymphoid organs can be examined as well as the level of anti-FSP immune response over the course of their disease. If CCDI can collect and share data from comprehensive analyses of molecular and immune profiling of children with CMMRD-associated cancers, it can lead to development of methods of early detection and monitoring of CMMRD tumors, and novel immuno-preventive or immuno-therapeutic strategies using FSP-based cancer vaccines in the future.


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Idea No. 994