Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium
| Autor: | David Malkin, Ashraf Shamvil, Matthew Mistry, Carol Durno, Steven Gallinger, Musa Alharbi, Shlomi Constantini, Qasim Alharbi, Melyssa Aronson, Eric Bouffet, Elizabeth Chao, Uri Tabori, Roula Farah, Hala Rimawi, Aaron Pollett, Derek Stephens, Ibrahim Qaddoumi, Doua Bakry, Cynthia Hawkins, Shay Ben-Shachar, Jordan Lerner-Ellis, Rina Dvir, Steve Kelies |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Oncology Cancer Research medicine.medical_specialty Pathology Adolescent Biology MLH1 DNA Mismatch Repair Neoplasms Internal medicine PMS2 medicine Humans Family history Child Adaptor Proteins Signal Transducing Mismatch Repair Endonuclease PMS2 Adenosine Triphosphatases Family Health Cafe-au-Lait Spots Infant Nuclear Proteins Cancer Microsatellite instability Syndrome medicine.disease Immunohistochemistry Pedigree DNA-Binding Proteins MSH6 DNA Repair Enzymes MutS Homolog 2 Protein MSH2 Child Preschool Mutation Female Microsatellite Instability DNA mismatch repair MutL Protein Homolog 1 |
| Zdroj: | European Journal of Cancer. 50:987-996 |
| ISSN: | 0959-8049 |
| DOI: | 10.1016/j.ejca.2013.12.005 |
| Popis: | Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited.We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented.Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive.CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children. |
| Databáze: | OpenAIRE |
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