Position paper: Challenges and specific strategies for constitutional mismatch repair deficiency syndrome in low‐resource settings

Abstract

Germline biallelic mutations in one of the mismatch repair genes, mutS homolog 2, mutS homolog 6, mutL homolog 1, or postmeiotic segregation increased 2, result in one of the most aggressive cancer syndromes in humans termed as constitutional mismatch repair deficiency (CMMRD). Individuals with CMMRD are affected with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood without specific interventions. The most common tumors observed are central nervous system, hematological, and gastrointestinal malignancies. The incidence of CMMRD is expected to be high in low‐resource settings due to a high rate of consanguinity in these regions, and it is thought to be underrecognized and consequently underdiagnosed. This position paper is therefore important to provide a summary of the current situation, and to highlight the necessity of increasing awareness, diagnostic criteria, and surveillance to improve survival for patients and family members.

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

“…Relatively simple but consistent follow-up with fewer modalities may still improve outcome for this devastating syndrome. 35 …”

Immune Checkpoint Inhibition as Single Therapy for Synchronous Cancers Exhibiting Hypermutation: An IRRDC Study

“…Traditional chemoradiation results in a median survival of 8-9 months in metastatic colorectal cancer, 16 9-13 months in metastatic TCC, 17 and < 6 months in CMMRD gliomas. 11 Treatment of cancers in CMMRD is inherently challenging, 18 because of resistance to alkylating agents like temozolomide and mercaptopurines 6 used in the treatment of GBM, colon, and urothelial cancers. However, as these cancers are inherently hypermutant 7 and exhibit high MS-indels, 14 ICI is more commonly used for these individuals at relapse.…”

Upfront Adjuvant Immunotherapy of Replication Repair–Deficient Pediatric Glioblastoma With Chemoradiation-Sparing Approach

“…1 Importantly, primary RRD gliomas are intrinsically resistant to temozolomide because of the absence of a functional mismatch repair (MMR) system necessary for this agent to achieve its cytotoxic effect. 5,6 Indeed, temozolomide therapy leads to acquired DNA MMR deficiency and this is a mechanism of resistance in recurrent GBM, contributing to an aggressive hypermutator phenotype. 7 Despite efforts to increase efficacy by combining irradiation-and chemotherapy-based approaches, GBM in children remains almost uniformly fatal following recurrence after this current standard therapy.…”

“…4 An increasingly recognized subset of pediatric GBM originates from errors in the DNA replication repair pathway (RRD). 5,6 RRD can be of germline origin, especially in young patients, or somatic, originating from the effects of previous treatment and rarely arising sporadically. From a genomics standpoint, RRD stems from DNA mismatch repair deficiency (MMRD) driven by mutations in one of the PMS2, MLH1, MSH2, and MSH6 genes and/or DNA polymerase proofreading deficiency (PPD), driven by mutations in POLE or POLD1 genes.…”