Chandrika Kurpad, MS, LGCG - CGA-IGC Communications Committee
A landmark study published in The Lancet Oncology has provided unprecedented insights into constitutional mismatch-repair deficiency (CMMRD) syndrome, a rare genetic condition that dramatically increases cancer risk in children and young adults.
This international collaborative effort, led by researchers from the International Replication Repair Deficiency Consortium (IRRDC), represents the largest and most comprehensive analysis of CMMRD to date.
What is CMMRD?
CMMRD is caused by inherited mutations in both copies of one of the mismatch-repair genes, which are crucial for correcting errors during DNA replication. This leads to a rapid accumulation of mutations throughout the genome, dramatically increasing cancer risk.
Study Details
The research team analyzed data from 201 patients across more than 50 countries. They collected comprehensive clinical information, performed genetic analyses, and examined the genomic features of 339 cancers that developed in these patients.
Key Findings
High Cancer Risk: The study found that patients with CMMRD have a staggering 90% chance of developing cancer by age 18, and 100% by age 40. This makes CMMRD one of the most aggressive cancer predisposition syndromes known.
Diverse Cancer Types: While CMMRD is known to cause brain tumors, gastrointestinal cancers, and blood cancers, the study identified a broader spectrum of cancer types, including some not previously associated with the syndrome.
Genetic Insights: The research revealed that the specific mismatch-repair gene affected (MLH1, MSH2, MSH6, or PMS2) influences cancer risk, type, and patient outcomes. Patients with MLH1 or MSH2 mutations tended to have earlier cancer onset and worse outcomes.
Genomic Landscape: CMMRD cancers showed extremely high mutation rates and specific mutational signatures, which could guide diagnosis and treatment decisions.
Treatment Implications: The study found that cancer surveillance programs and immunotherapy treatments improved survival rates, but their effectiveness varied depending on the specific gene mutation.
Implications for Patient Care
Early Diagnosis: The study highlights the importance of early genetic testing for children with certain cancer types or specific non-cancerous features that overlap with other syndromes like neurofibromatosis type 1.
Tailored Surveillance: The findings suggest that cancer screening programs should be tailored based on a patient's specific genetic mutation.
Personalized Treatment: The effectiveness of immunotherapy varied depending on the affected gene, emphasizing the need for personalized treatment approaches.
Adult Screening: As more patients survive into adulthood, the study suggests a need for continued screening for adult-onset cancers.
Future Directions
This comprehensive study lays the groundwork for improved diagnosis, surveillance, and treatment of CMMRD. It also opens up new avenues for research into cancer prevention and targeted therapies for this highly aggressive syndrome.
The international collaboration demonstrated in this study highlights the importance of global efforts in understanding and treating rare genetic disorders. As our understanding of CMMRD grows, there is hope for better outcomes for affected individuals and families worldwide.
For more information, the full study can be found in The Lancet Oncology (DOI: 10.1016/S1470-2045(24)00026-3).
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If you want to access more pediatric-related content, read our blog post or watch our joint webinar with NASPGHAN about "Constitutional mismatch repair deficiency syndrome."
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