The international BMMRD consortium is committed to highly collaborative research among clinicians and scientists from 5 continents. This research includes clinical studies to better understand the issues which are involved in BMMRD, basic concepts of mismatch repair deficiency and the corresponding cancers and translation of these observations into therapies for children with BMMRD.
- Modeling DNA Replication Repair Deficiency in Zebrafish
- Modeling DNA Replication Repair Deficiency in Mice
- Immunotherapy—Checkpoint Blockade
Defining the spectrum of BMMRD cancers and their outcome is an ongoing effort. In recent years, important papers form the European group (C4CMMRD, J Med Genet 2014), the French group (Lavoine et al. J Med genet 2015) and the international BMMRD consortium (Backry et al, EJC 2014) have reinforced the role of malignant gliomas, haematological malignancies and gastrointestinal cancers as the most common cancers in BMMRD.
Ongoing research and data collection uncovered other less common cancers in children and common adult cancers such as breast cancers and genitourinary malignancies in adult survivors of BMMRD. These findings have specific implications on the surveillance protocol.
We also uncovered that although the prevalence of BMMRD is unknown, in some areas of the world, such as the Middle-East and South Asia, BMMRD can be common and present a huge burden of cancers such as malignant brain tumors (Amayiri et al. IJC 2015).
Finally, the surveillance protocol implemented by the Consortium and the European group has resulted in encouraging long term survival benefits (Durno et al. PBC 2012, EJC 2015) as well as impact on the gastrointestinal phenotype of BMMRD patients (Aronson et al. Am J Gastroenterol 2016).
BMMRD patients are at a high risk for multiple malignancies throughout childhood. Therefore, a screening protocol was devised and implemented by the Consortium and others, with the goal of intervening at an early tumor stage. Recent data reports that BMMRD patients that undergo screening experience improved outcomes. Through use of the screening protocol, BMMRD patients are reaching adulthood for the first time.
We continue to monitor and collect surveillance data of BMMRD kindred 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.
BMMRD is ultimately diagnosed by identifying a germline mutation on both alleles of one of four mismatch repair genes (MSH2, MSH6, MLH1, PMS2). However, 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. We have shown that microsatellite instability (MSI) is not a reliable predictor of BMMRD, 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. Novel diagnostic tools include immunohistochemistry staining for the four MMR genes in both normal and tumor tissue, functional assays 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 do not incur the cost of traditional sequencing.
The Consortium (Shlien et al, Nature Genet 2015) and the European group (Bodo et al. gastroenterology 2015) are working on developing robust and rapid tools to molecularly diagnose BMMRD to enable early detection of cancers and management of these patients.
Using normal and tumor tissues from members of the Consortium, we were able to uncover that BMMRD cancers have the highest mutational load among all human cancers (Shlien et al, Nature Genet 2015). We have 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 with other scientists to study other aspects of BMMRD tumors such as the effect of hypermutation on RNA and on DNA methylation.
We are developing animal models to study the mechanisms of cancer initiation and progression in BMMRD. We also use patient derived xenograft tumors to test new drug therapies as preclinical models before proceeding to clinical trials.
One of the models we are using is zebrafish, a tropical fish that has received tremendous 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 zebra fish has two objectives: 1) to model the human BMMRD-driven cancers that lack replication repair and 2) 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.
The absence of animal models of BMMRD brain tumors has proved a barrier for rapid testing of drug efficacy. We are currently in the process of designing and characterizing a mouse model of these malignant brain tumors. Although the Consortium has made incredible strides in identifying key characteristics of the brain tumors arising in our patients, such as ultrahypermutation and secondary somatic mutations in polymerase proteins, such a model will be invaluable to further our understanding of biological mechanisms that drive BMMRD cancers.
Immunotherapies that target and inhibit 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 that connects 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 characteristic 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 BMMRD brain tumors harbor the highest mutation load of all paediatric cancers and certainly most adult cancers, this makes them susceptible to immunotherapies such as Nivolumab.
Our group is currently working to characterize the immune response provoked by this treatment by using novel tools to gain greater resolution and identify key immune factors responsible for such a response. This will allow us to determine how and if a patient will benefit from immunotherapy.
Based on our translational data, we recently observed encouraging response to a new type of immunotherapy called immune checkpoint inhibitors. Recurrent glioblastoma from BMMRD patients with hypermutation responded to the immune checkpoint inhibitor Nivolumab (Bouffet et al. JCO 2016).
In order to test new treatments for BMMRD, the international BMMRD Consortium is supporting two new international clinical trials which will test response to immune checkpoint inhibition in recurrent BMMRD cancers. These trials will open soon.
Biological correlative studies will be performed to determine the reasons for response or lack of for these therapies.
For further information on clinical trials please contact us.
For ongoing research publications and updates related to BMMRD please log on to PubMed.