The IRRDC is an international collaborative research initiative which aims to better understand and manage this rare genetic condition.

Through collecting biological and clinical data of affected individuals and family members, molecular genetic analysis, patient screening and laboratory research, we continue to increase our understanding of this complex genetic syndrome. Since the establishment of the Consortium, the number of Consortium members is growing, and now includes clinicians, scientists, genetic counsellors, medical professionals, psychologists and patient advocates.

Please see below for some of our current research objectives:

Defining the spectrum of CMMRD cancers and their outcome is an ongoing effort. During the last decade, important papers from the European group (C4CMMRD, J Med Genet 2014), the French group (Lavoine et al. J Med genet 2015) and the international CMMRD consortium (Bakry et al, EJC 2014) identify malignant gliomas, haematological malignancies and gastrointestinal cancers as the most common cancers in CMMRD.

Ongoing research and data collection revealed other less common cancers in children, and common adult cancers such as breast cancers and genitourinary malignancies in adult survivors of CMMRD. These findings have specific implications on the surveillance protocol (Tabori et al. Clin Cancer Res. 2017).

Although the prevalence of CMMRD is unknown, we’ve found that in some areas of the world, such as the Middle-East and South Asia, CMMRD can be common and present cancers such as malignant brain tumors (Amayiri et al. IJC 2015).

In 2021, a working group created during our Annual Workshop in 2017 established seven diagnostic criteria for the diagnosis of CMMRD. The criteria incorporate germline mismatch repair results, ancillary tests and clinical manifestation to determine a diagnosis, and provides updated guidelines for healthcare providers (Aronson et al. J. Med. Genet. 2021)

CMMRD patients are at high risk for multiple malignancies throughout childhood. Therefore, a screening protocol was developed and implemented (Tabori et al. Clin Cancer Res. 2017) with the goal of intervening at an early tumor stage.

Through the screening protocol, CMMRD patients are reaching adulthood for the first time.

We’re monitoring and collecting surveillance data of CMMRD patients to ensure the long term follow up for those patients and families, and to further refine surveillance strategies to improve clinical outcomes and quality of life of our patients and families.

In 2021, we published a landmark study looking at the efficacy of this protocol in 193 tumours from 110 patients enrolled in our research registry (Durno, Ercan, Bianchi et al., 2021). The surveillance protocol was found to be strikingly effective. For patients undergoing surveillance, 100% of GI and solid tumours, and 75% of brain tumours were identified asymptomatically. In addition, the overall benefits of the surveillance protocol were clear. Four-year survival was 79% for patients who adhered to the full protocol, and 55% for patients who underwent partial surveillance. In contrast, survival was only 12% for patients not under surveillance. These results suggest that even partial surveillance confers a huge survival benefit to patients with CMMRD.

A bar graph comparing survival (y) over time (x) for CMMRD patients. The graph compares full surveillance (blue), partial surveillance (green) and no surveillance (yellow). Survival decreases over time for all groups, but overall survival is much higher for full surveillance than no surveillance patients.

Patients undergoing full or partial surveillance show significantly higher survival than those undergoing no surveillance

CMMRD is diagnosed by identifying a germline mutation on both alleles of one of four mismatch repair genes (MSH2, MSH6, MLH1, PMS2). But clinical sequencing can be costly and problematic, particularly in the case of PMS2, for which many pseudo genes exist that interfere with the correct identification of a mutation.

The MS-sigs tool can detect CMMRD with 100% specificity and sensitivity

We’ve shown that “traditional” microsatellite instability (MSI) is not a reliable predictor of CMMRD, as it is in Lynch syndrome. Therefore, the Consortium has been addressing the need for accurate and sensitive diagnostic tools since its conception.

The use of more accessible and highly sensitive diagnostic tools have been tested and validated by the Consortium and others. New diagnostic tools include immunohistochemistry staining for the four MMR genes in both normal and tumor tissue, functional tests that measure a patient’s ability to repair mismatches, and a patient’s cell line response to chemotherapeutics that require MMR function. These tools can be implemented from a simple blood draw or skin biopsy, and don’t incur the cost of traditional sequencing.

In 2020, the IRRDC developed a new tool known as MS-sigs using a large cohort samples that were collected through our registry (Chung et al., 2020, Cancer Discov). MS-sigs is an inexpensive and robust assay that can be used to screen both normal and tumour cells for CMMRD. It requires very little DNA (about the amount found in a finger prick) and is cheap to run. MS-sigs it is also able to detect CMMRD in both normal and cancer samples, which lets patients get diagnosed before they develop their first cancer. This gives them time to start early surveillance protocols and improves their overall survival. Over the next year, we will work to transform MS-sigs into a frontline tool that will improve the clinical diagnosis of CMMRD throughout the world.

Using normal and tumor tissues from members of the Consortium, we found that CMMRD cancers have the highest mutational load among all human cancers (Shlien et al, Nature Genet 2015). We’ve also uncovered secondary somatic mutations in genes such as DNA polymerase E and D which cause this hypermutant phenotype. Current research is focused on ways to use this phenomenon as a weakness of these cancers and to develop new therapies aiming at hypermutation.

The Consortium is collaborating to study other aspects of CMMRD tumors, such as the effect of hypermutation on RNA and on DNA methylation (Dodgshun et al., Acta Neuropathol. 2020).

In 2017, we (Campbell et al., Cell, 2017) published a paper that had significant impact on our understanding of hypermutant tumours:

  • New drivers of hypermutation in POLE and POLD
  • Timing of replication repair deficiency determines mutation signature composition
  • Germline replication repair deficiency can be identified from tumour-only sequencing
  • Mutation burden and signatures have value for screening, surveillance, and therapy

The absence of animal models of CMMRD brain tumors is a barrier for rapid testing of drug efficacy.

We’ve designed and characterized multiple new mouse models of these malignant brain tumors. Such models have been crucial to further our understanding of biological mechanisms driving CMMRD cancers.

In 2020, our group (Galati et al. Cancer Res. 2020) published a new study, where we established mouse models harboring cancer-associated POLE mutations P286R and S459F. Cancers driven by these mutations displayed striking resemblance to the human ultrahypermutation and specific signatures making them an excellent model to learn more about the human syndrome. Furthermore, the cancers that developed in these models were heterogenous, much like in humans. These findings ultimately provided insights into the carcinogenesis of POLE-driven tumors and will provide valuable information for genetic counseling, surveillance, and immunotherapy for patients.

One of the models we are using to model CMMRD and RRD is zebrafish, a tropical fish growing in popularity as a scientific model due to its fast-breeding time, transparency at its embryonic and larval stages, and the conservation between humans and zebrafish in disease-related genes.

The modeling of DNA replication repair deficiency in zebrafish has two objectives:

  • To model the human CMMRD-driven cancers that lack replication repair
  • To conduct a high-throughput drug screen to identify potential therapeutics that can overcome the intrinsic drug resistance of cells that do not have replication repair

Immunotherapies targeting and inhibiting immune checkpoints have recently shown efficacy in individuals with metastatic melanoma, non-small cell lung carcinoma (NSCLC) and mismatch repair deficient colorectal cancers (Lynch Syndrome).

The underlying biology connecting these cancers is their high rates of mutation. We now know that this increased mutation load causes these cancers to display higher numbers of neoantigens. This means that the tumors are more likely to be detected as “non-self” and thus be targeted and attacked by the body’s immune system. Since CMMRD brain tumors harbor the highest mutation load of all paediatric cancers, as well as most adult cancers, this makes them susceptible to immunotherapies such as Nivolumab.

Our group is currently working to characterize the immune response triggered by this treatment through new tools to gain better knowledge and identify key immune factors responsible for the response. This allows us to determine how and if a patient will benefit from immunotherapy. Were also investigating how immunotherapy functions when combined with other novel agents.

We were the first to show that CMMRD cancers can disappear when treated with ICI (Bouffet et el. J Clin Oncol. 2016). More recently, we were able to see the first objective and durable long-term survival in >50% of patients treated with ICI.

The next horizon is to identify new “targeted” therapies that can be combined with ICI to improve survival even further. In 2021, we uncovered that hypermutant cancers are enriched for mutations in the RAS/MAPK pathway (Campbell, Galati et al. Cancer Discovery. 2021). When we treated patients with a combination of “targeted” MEK inhibitors and ICI, we observed durable responses to ICI in combination with targeted therapy.