{"id":254,"date":"2020-12-22T20:12:11","date_gmt":"2020-12-22T20:12:11","guid":{"rendered":"https:\/\/lab.research.sickkids.ca\/tabori\/?page_id=254"},"modified":"2022-01-25T19:05:41","modified_gmt":"2022-01-25T19:05:41","slug":"replication-repair-deficiency","status":"publish","type":"page","link":"https:\/\/lab.research.sickkids.ca\/tabori\/research\/replication-repair-deficiency\/","title":{"rendered":"Replication Repair Deficiency"},"content":{"rendered":"

Replication Repair Deficiency Research<\/h2>\n

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The International Replication Repair Consortium (IRRDC)<\/span> is an international collaborative research initiative run by our group which aims to better understand and manage this rare genetic condition. <\/span>\u00a0<\/span><\/p>\n

Through collecting\u00a0<\/span>biological and clinical data of affected individuals and family members, molecular genetic analysis, patient screening and laboratory research<\/span>,<\/span>\u00a0we continue to increase our understanding of this complex genetic syndrome. Since the establishment of the Consortium, the number of Consortium members is growing<\/span>,\u00a0<\/span>and now includes clinicians, scientists, genetic counsellors, medical professionals, psychologists and patient advocates.<\/span>\u00a0<\/span>\u00a0<\/span><\/p>\n

Our Research Initiatives Include:<\/p>\n

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Clinical Research<\/h3>\n

Defining the spectrum of CMMRD cancers and their outcome is an ongoing effort. In recent years, important papers f<\/span>r<\/span>o<\/span>m the European group (C4CMMRD, J Med Genet 2014), the French group (<\/span>Lavoine<\/span>\u00a0et al. J Med genet 2015) and the international CMMRD consortium (<\/span>Backry<\/span>\u00a0et al, EJC 2014)\u00a0<\/span>identify\u00a0<\/span>malignant gliomas,\u00a0<\/span>haematological<\/span>\u00a0malignancies and gastrointestinal cancers as the most common cancers in CMMRD.<\/span>\u00a0<\/span><\/p>\n

Ongoing research and data collection\u00a0<\/span>revealed\u00a0<\/span>other less common cancers in children<\/span>,<\/span>\u00a0and 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).<\/span>\u00a0<\/span><\/p>\n

Although the prevalence of CMMRD is unknown, we<\/span>\u2019<\/span>ve found that in some areas of the world, such as the\u00a0<\/span>Middle-East<\/span>\u00a0and South Asia, CMMRD can be common and present cancers such as malignant brain tumors (<\/span>Amayiri<\/span>\u00a0et al. IJC 2015).<\/span>\u00a0<\/span><\/p>\n

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Establishing Effective and Feasible Surveillance Programs<\/h3>\n

CMMRD patients are at high risk for multiple malignancies throughout childhood. Therefore, a screening protocol was de<\/span>veloped<\/span>\u00a0and implemented (Tabori et al. Clin Cancer Res. 2017) with the goal of intervening at an early tumor stage. Recent data\u00a0<\/span>suggests that\u00a0<\/span>CMMRD patients that undergo screening experience improved outcomes.<\/span>\u00a0<\/span><\/p>\n

Through the screening protocol, CMMRD patients are reaching adulthood for the first time.<\/span>\u00a0<\/span><\/p>\n

We<\/span>‘re monitoring and collecting<\/span>\u00a0surveillance data of CMMRD\u00a0<\/span>patients\u00a0<\/span>to ensure the long term follow up for those patients and families<\/span>,<\/span>\u00a0and to further refine surveillance strategies to improve clinical outcomes and quality of life of our patients and families.<\/span>\u00a0<\/span><\/p>\n

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New Diagnostic Approaches<\/h3>\n

CMMRD is diagnosed by identifying a germline mutation on both alleles of one of four mismatch repair genes (<\/span>MSH2, MSH6, MLH1, PMS2<\/span><\/i>).\u00a0<\/span>But<\/span>\u00a0clinical 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.\u00a0<\/span>\u00a0<\/span>\u00a0<\/span><\/p>\n

We<\/span>\u2019<\/span>ve shown that 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.<\/span>\u00a0<\/span><\/p>\n

\u00a0<\/span>The use of more accessible and highly sensitive diagnostic tools\u00a0<\/span>have<\/span>\u00a0been tested and validated by the Consortium and others. N<\/span>ew<\/span>\u00a0diagnostic tools include immunohistochemistry staining for the four MMR genes in both normal and tumor tissue, functional\u00a0<\/span>tests\u00a0<\/span>that measure a patient\u2019s ability to repair mismatches, and a patient\u2019s cell line response to chemotherapeutics that require MMR function. These tools can be implemented from a simple blood draw or skin biopsy<\/span>,<\/span>\u00a0and do<\/span>n\u2019<\/span>t incur the cost of traditional sequencing.<\/span>\u00a0<\/span><\/p>\n

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Basic and Translational Research<\/h3>\n

Using normal and tumor tissues from members of the Consortium, we\u00a0<\/span>foun<\/span>d<\/span>\u00a0<\/span>that CMMRD cancers have the highest mutational load among all human cancers (<\/span>Shlien<\/span>\u00a0et al, Nature Genet 2015). We<\/span>\u2019<\/span>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.<\/span>\u00a0<\/span><\/p>\n

The Consortium is collaborating to study other aspects of CMMRD tumors<\/span>,<\/span>\u00a0such as the effect of hypermutation on RNA and on DNA methylation.<\/span>\u00a0<\/span><\/p>\n

W<\/span>e\u2019<\/span>re developing animal models to study the mechanisms of cancer initiation and progression in CMMRD. We also use patient<\/span>–<\/span>derived xenograft tumors to test new drug therapies as preclinical models before\u00a0<\/span>moving\u00a0<\/span>to clinical trials.<\/span>\u00a0<\/span><\/p>\n

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Modeling DNA Replication Repair Deficiency in Zebrafish<\/h3>\n

One of the models we<\/span>\u2019<\/span>re using is zebrafish, a tropical fish\u00a0<\/span>growing in<\/span>\u00a0<\/span>popularity as a scientific model due to its\u00a0<\/span>fast-breeding<\/span>\u00a0time, transparency at its embryonic and larval stages, and the conservation between humans and zebrafish in disease-related genes.<\/span>\u00a0<\/span><\/p>\n

\u00a0<\/span>The modeling of DNA replication repair deficiency in zebrafish has two objectives:\u00a0<\/span>\u00a0<\/span><\/p>\n